Has anyone traveled through Italy by car?

Yes, I have done this. No, I don't recommend it, unless maybe you have a carful of kids, or want to visit unnamed towns that are not served by train.

Yes, you can pick and drop a rental car in different cities of Italy with no penalty; see AutoEurope or sister company Kemwel.

If you have not already booked a return flight from Milan, then consider booking it from Naples or Rome on a "multi-city" or open-jaw itinerary.

No, I would not stay in Mestre; if driving, park at Tronchetto (€21/day) and take a vaporetto toward your Venice hotel, just as you would do if you arrived by train at S. Lucia station.

Why are you renting a car in the first place in the locations you mentioned? You can't use it at all, except for the Amalfi Coast.
Venice is for boats only. Florence is forbidden to cars except those with resident permit, Cinque Terre is also largely forbidden to cars and parking is non existent except for Monterosso, where you would keep it parked the whole time anyhow.
In your shoes I would take a train from Milan to Venice (no car needed there). Then I would take a train from Venice to Florence (no car needed in Florence).
Once in Florence, if you want to visit the Tuscan countryside, then I would rent a car. Get out of Florence and visit Tuscany by car, then drive to the Cinque Terre.
At the Cinque Terre you won't need a car either, but if you stay only a couple of days and want to go to the Amalfi Coast by car, you could keep it parked in Monterosso, then you can drive from Monterosso to the Amalfi Coast.
For the return trip by air, you should look for a flight out of Rome, instead of going all the way back to Milan.

You said: " I would appreciate any tips related to car travel in these areas!" and you're getting tips that say, in essence, "Don't."

Can you tell us why you are planning to rent a car? Was it because you imagine the drives between these locations as being picturesque and more enjoyable from a car than from a train? Were you aware that the drive from Florence to Amalfi is at least 5 1/2 hours without traffic and without any stops? And it's a minimum of 9 hours from Amalfi to Milan, again without traffic and with no stops.

We spent a month in Italy driving around, we drove from Rome, generally north to venice ( via the tuscany), then across to lake como, then down to Cinque T and then over to Monaco and onwards. I deliberately visited Amalfi via train ( fast train from Milan to naples then back to Rome)
we stopped outside Florence at Fieslo, stayed at Jesolo lido outside venice ( great spot to stay, look it up) and stayed at levanto outside CT.

IMO, going anywhere near the major tourist areas with a car ( if you are not prepared for it) is asking too much as a traveller, when there are other options.
we would stay in good accommodation ( that was often much cheaper), with parking, outside these areas, and just catch the bus into town. it worked great and you got to see how the locals get around by bus/train.

think seriously about your options.

Milan and pick up a rental car then plan to drive to Venice, Cinque Terre, Florence, and Amalfi Coast and return car to Milan.

Oh dear.

Is there a reason that you must have a car? All the places you have names are awful by car and very easy by train. Trains planned well in advance can be extremely inexpensive in Italy.

Milan
Some of the worst times I have had on the Autostrada are on that one between Milan and Venice, particularly around Milan, Verona and on the approach to Venice. There are so many trucks on that route, many of them either foreign or on the way to foreign countries, that they form an almost impenetrable wall which blocks the views of the exits and makes it difficult to get off.

Don't speed, you won't know where the cameras are, and the Tutor system which watches that highway averages your speed and sends out tickets automatically.

The toll is quite high.

Don't stay in Mestre. Stay in one of the most beautiful cities of the world.

Parking, ZTLs, tolls, fuel (some of the very most expensive in Europe - usually the highest), and extra costs make driving in Italy very expensive and stressful.

Cinque Terre
5 villages overflowing with tourists and cruise ship trippers, with extremely narrow streets which are mostly off limits to tourist cars, and with remote parking at the end of a narrow one lane road. Much easier by train.

Florence
The king of the ZTLs. It is easier to get an expensive ticket (in the mail many months later after the car place has told them who you are and taken a substantial fee for so doing) there than anywhere else that I know.

Amalfi Coast
That's a lot of tolls from Florence. The A1 is not cheap, and the traffic rules change dramatically when you reach the Naples area. My wife was literally cowering at many of the intersections.
I've driven the coast road well out of season. It is not easy the, and parking is practically impossible (that was April). I can't imagine what it would be like in high season.

Why back to Milan? It will cost you a fortune.

But, like we always say, it's your vacation.

Enjoy.

We have driven through out europe and the nation which provided the least driving satisfaction was Italy. There simply are too many hassles and not enough rewards to merit car rental in Italy, especially given very good public transport avails itself to meet a travelers needs.

Interesting! The reason for renting a car is for the freedom, and for ease of transporting luggage, and for the picturesque drives between locations.

Are trains available from Amalfi to Milan? Our flight is booked in and out of Milan.

If you want a car for the freedom to go to smaller towns not served by train or to make many more stops along the way, then it offers that. If you want to travel conveniently between the cities listed, then trains running at least hourly provide enough freedom for most people. Scenery is the same from a major highway or major rail line; it only improves if you again choose some more rural destinations. Luggage handling is also not improved, since you will rarely be able to park near your hotel in these areas, and often can't even drive to them. I don't think a hotel in Mestre is a good tradeoff just to be able to park closer. Do try to pack light, to ease your luggage handling concerns.

If you end up taking a car to Venice, park in Mestre and ride the train the short distance into Venice. (or at least check the prices online and see how much you would save) We parked in Mestre for 3 days and it cost less than 1/2 of what parking at the big parking garage in Venice. It cost us euro each way per person to ride the train over the causeway. This was in 2008, which is why I advise you doing your own research into the current prices.

Thank you all for your valuable input! I'll reconsider the use of a car. Laura, the RS website has a map of Italy that shows the train routes between all Italian cities and their train fare. I can't seem to locate it again. Can you help with that?

I'm going to go out on a limb here and make a wild guess that you have not traveled in Europe much before. I base that on the way you phrased your original question ("Can you pick up a car in one city and return car in another city?") and the general notion that one would fly into Milan and drive most of the length of Italy...I think most experienced travelers would recognize that as a recipe for misery.

Some parts of Italy (like many parts of Europe) are best done by train. In other parts (true for both Italy and Europe as a whole), a car can give you flexibility and freedom (as you suggest), and can open up wonderful areas that are not well served by trains. But it's critically important to know which places fall into which category.

IMHO Every place you mention, without exception, falls into the bucket of "great and easy by train, a nightmare by car."

Your stated justifications for car travel on this trip are not grounded in the real world:
1. Freedom - Your car will be a major, expensive headache in all of the places you say you're going. It will be the opposite of freedom - it will be a ball-and-chain to which you are shackled. You can not use a car in those places. You can only use it to get within the outskirts of those places, where you will have to leave it, paying to park it while you are free FROM it.
2. Ease of transporting luggage. A car is the wrong medicine for this condition. If you have that much luggage that you can't easily take it with you on a train....you packed too much. Be disciplined about how much stuff you bring, that is the solution to "ease of transporting luggage".
3. Picturesque drives between locations. Most of the time in-between is going to look like US interstate highways - and not the pretty ones. While much of Italy is beautiful, a lot of it is not much better than New Jersey.

I would seriously reconsider your plans. Take trains to link your destinations, you will enjoy your time so much more. If there is some area (say, Tuscany) that you really want to have the freedom to wander through, then rent a car for a few days there. But for all the places you mention, a car sounds like a really, really bad idea to me. And I like cars.

Finally, the road along the Amalfi coast is every bit as spectacular as you expect it will be, but it is best seen as a passenger in someone else's vehicle (a bus, or the boat). I enjoy a nice drive as much as anyone, but the traffic is so heavy there is no enjoyment to be had there.

The best way to travel in Europe is not by car or by train, rather, it is often a combination of the two.

Although a car is not a good idea for many of the places you intend to visit, however a car is definitely a great choice to visit the small towns and the countryside of Tuscany. Consider this itinerary:

MILAN > VENICE (by train)
VENICE > FLORENCE (by train)
FLORENCE: After visiting Florence rent a car. Use the car for visiting Tuscany for a few days. Choose a base somewhere between Florence and Siena.
TUSCANY > CINQUE TERRE (by rental car)
At the Cinque Terre you won't need a car, therefore a good option is to return the car to nearby LA SPEZIA, then reach the Cinque Terre by train (10-15 min).
CINQUE TERRE > AMALFI COAST (by train or, if you decided to keep the car, by car). The trip is long no matter what you use.
AMALFI COAST > MILAN (train or car). It's another very long trip. The train is faster however.

I like to have a car, but others, especially Americans, don't because they find driving the narrow Amalfi road too challenging. Also parking is expensive. So I'll leave that to you.

Here is the perspective from someone who rents a car a lot of the time, simply for the reason you stated... freedom. I have driven all the areas you want to drive and given that it looks like you really just want to go point to point I would not bother with a car except for Roberto's suggestion. I am assuming you are talking about travel in the summer? And will you have hotel reservations? If so, there is really no reason for the car. The drives between your locations are not particularly beautiful. The Amalfi coast drive, although gorgeous, can be a real headache. It is crowded and the road is narrow. I did it, but it was not pleasurable and would not bother again.

As for Tuscany I would have the car to travel the countryside and explore small villages, etc. If at all possible stay in Venice proper. My first trip there I had a car, and it was a spontaneous decision to go to Venice, so I stayed in Mestre. It was fine, but nothing like staying right there.

In Tuscany the beauty of a car is that it lends itself to spontaneous decisions, roadside picnics, exploring vineyards... in your other locations it will be a drawback.

Rick’s Train Travel Time & cost Map gives you an overview of faster train travel times in hours, as well as regular 2nd-class fares. Advance discounts are also available, but if freedom for you means not locking in departure times, then you can buy tickets in the stations as you go for the rates shown, or buy a couple of tickets at any particular stop. (Naples to Amalfi is served a separate selection of relatively affordable local train, bus, or ferry companies.)

How to Look Up Train Schedules and Routes Online gives you the DB train schedule link and tips for using it.

Wow, if Terry Kathryn says no car, that seals the deal. Terry Kathryn is a big fan of car travel in Europe and almost always prefers it to the train. If she says train is the way to go on this trip, that's serious.

If you need more convincing about the perils of driving in Italy anywhere near big cities, read this thread (merely the most recent one of many): https://community.ricksteves.com/travel-forum/transportation/avoiding-traffic-fines-in-italy

And if you're still thinking of driving, learn what a ZTL is. You'll either learn before your trip, or learn the expensive way months later.

susie,

I definitely agree with the others that travel by train will be far easier, more efficient and less stressful than by car for most of the places you're visiting. Especially in Naples and the south at this time of year, traffic could be brutal and the locals in that area seem to consider traffic laws more of a "guideline" so it's not like driving anywhere else.

It would help to know if you're already got your flights booked into Milan?

There are potentially expensive "caveats" with either rental cars or using public transit, and you'll need to be aware of those for trains if you decide to go that route. If you need more information, post another note. The easiest way to find the costs and other details for trains is to use the Trenitalia website.

You may find this recent Thread of interest......

https://community.ricksteves.com/travel-forum/transportation/avoiding-traffic-fines-in-italy

Harold beat me to it. Take Terry Kathryn's car advice as gospel.

Ok... I do usually prefer a car.... but not ALWAYS! :) I am just not as opposed to it as many here are!

Just don't come back and use this against me!

I did advocate for the car in Tuscany....

I don't know where you are flying from but it is seriously unwise to be arriving from the States or Australia and immediately hoping in a car after an all night flight. Think of the rest of us on the road. Of course if you are flying from London, disregard this.

We have driven a lot in Italy and the advice you are getting is sound. You don't need a car for most of your itinerary and it would be an expensive annoying hassle to have one. If you plan to spend a few days in Tuscany then a car there would be a necessity, but do read up on the rules of the road in Italy and particularly ZTL restrictions.. Basically every charming town in Tuscany is barred to cars so you would need to park on the outskirts and walk.

It is also seriously unwise to travel with your luggage. I know of someone who lost it all when parked at a beach in Italy. If you do stop along the way with everything in the car, make sure nothing is in the cabin of the car as in NOTHING and do not open the trunk at the destination. Carry the computer, the cameras, the money, the ID even if the stop is for lunch. Never risk leaving major valuables in the trunk.

And finally, you need to be in Milan the night before your trip home, so if you plan to do any touring of Milan do it last. Traveling from the Amalfi coast to Milan the day of your flight whether by bus/train or by car is a disaster waiting to happen. The cost of a walk up one way ticket home, particularly if you are heading to the US or Oz is enormous.

susie, if you do have any issues with organising your travel plans, you might want to consider doing either CT or Amalfi Coast. No doubt there are a stack of forum posts on someone liking one area over another. having been to both (CT by car) they both take some organising to get there. we spent about 5 days at each area, staying in Sorrento at Amalfi and Levanto at CT.
If we were asked which one we liked we would say the Amalfi, hands down. Yes there are plenty of tourist, but there is so much to see, in the area. and absolutely beautiful scenery.
we found at CT the towns are only very small and hence don't take long to walk around and travelling around between towns 'can' be problematic ( if our experience was any indication) luckily we had a good day to catch a ferry along the coast ( the next few days the ferry did not run) the trains were not running on time and so were filled with unknowning tourists ( including us) getting on wrong trains, missing towns etc, just a real mess.
some of the walking trails between towns were not open.
our general feeling of the towns was they would have been great many years ago, but looked like they were let go. ( different from being run down by tourists)
This was our experience, doesn't mean much to others I know ( before someone jumps down my throat and tries to tell otherwise)
we caught a fast train from milan to naples. we bought it on line in advance and got business class very reasonably, it took about 4 hours ( then local transport to Sorrento) if you do want to go that way.