Montepulciano to Cinque Terre - best way to get there

Where are you going after Cinque Terre and will you require the car?

Montepulciano to Pisa will take at least 2.5 hours by highway. Any scenic drive about 4 hours.

We will be taking the train to Milan to end our trip. I’m just trying to decide what the easiest method is. We don’t mind driving to Pisa but then where do we return car and how close to train station - trying to avoid too many logistical challenges.

The closest place where you could return the car is in La Spezia. All major companies have an office (mostly near the cruise port). After returning the car you'd take a taxi from the rental place to the La Spezia Centrale station from which you can take a train to the Cinque Terre village of your choice.

If you wish to stop in Pisa on the way to La Spezia you can. Below is where I usually park when I take people to see the leaning tower. Save the place in your phone.
https://maps.app.goo.gl/xbjVBjrbPawm5Vg56

You could also return the car in Pisa, however all rental offices in Pisa are at the airport. If you return the car at the Pisa airport, you would need to take the PisaMover people mover to the Pisa Centrale station, drop off your luggage at the luggage storage at the station, then go to see the tower and duomo (25 min walk or 10 min bus/taxi). Once you are done, you can return to the station, pick up your bags, then take a train to the Cinque Terre (most will require a train change at La Spezia).

I would not return the car in Florence, if you can. That would add time and hassle to the process.

Thank you. This is very helpful. Sounds like a good plan! Do you think it’s safe to leave our luggage in the car while we visit Pisa for a few hours? I keep reading about how it’s unsafe to leave valuables in your car at all.

Pisa is about the only place I would not leave luggage in the car in Italy (yes even in locked trunk). It is a pain, but the only true guarantee is to store your luggage.
If Pisa is not in the plan, then I would drop the car at La Spezia.

Leaving luggage in the trunk is always a risk. If you park where I told you, as soon as you enter the lot, on the first row to the right you have the ability to back the car against a fence. Even that it is not guarantee of no break in, since often thieves smash the window next to the back passengers' seats, then lower the back of the seat to access the trunk. Car break ins in Italy are not as frequent as here in San Francisco or Oakland (it's become so ridiculous here, that I don't go there at dinner anymore), however they do occasionally happen, so you should always take the most valuable luggage with you. Also, besides back the car against a wall/fence, I also put some stuff in the spare tire hold (which you cannot access from the passenger doors). I also scatter the items all over the trunk rather than putting it in the bags (it takes a second to grab a bag and run, but you can always take a few things a garment at the time). The safest alternative is a luggage service (like www.radicalstorage.com or bouncebag etc.). Valuable items such as electronic devices should always be with you.

Another alternative is to visit the sights taking turns. So for example if there are 4 of you travelling together, 2 visit the leaning tower while two stay in the car at the parking lot, then when the first two come back the other two go. The parking lot I indicated is 2 min walk from the tower and the rest of the sights.

Your choice.

Thank you all for your replies.
If we do park at the lot you mentioned in Pisa, is it easy enough to avoid ZTL zones? I’m so worried about that. It will be our first time driving in Italy! Thanks.

Just follow Google Maps directions and you'll be fine.
I would also take the route through via the SGC FI-PI-LI highway rather than the A1 > A11. The former is toll free and shorter in terms of miles, while the A1-A11 is longer and doesn't save any time is spite of the higher speed limits.

Thank you. So helpful. Really appreciate it.