Venice, Cinque Terre, Siena and Rome

It is a very full and fast survey trip. First, your questions:
yes you can pick up a car in one city and drop in another. Its called a one way rental. There is a small additional fee (maybe $40). Take a look at Autoeurope which is a car rental consolidator website that gives you rate from various companies for your route. I have used it many times because I find them to be cheaper than renting directly from the company, and they are very easy to work with and reliable. But if I dont find what you want, then check individual companies too.
As for the itinerary, I think the Tuscany part will give you little time to catch your breath in a place. It sounds like you will spend an evening in each Tuscany town? I would skip Montepulciano and drive straight to Orvieto and have more time there. So Venice, CT, Siena, Orvieto, Rome. That is a lot in 2 weeks. Consider that for each drive, parking will take a chunk of time, navigating crowded roads and figuring out where to go is not always clear, and sometimes you will park a ways away from your destination and walk in the heat for 15-20 minutes. There are parking lots with pay systems to navigate, and one way roads and wrong turns, and lots of other cars. None of this is hard, or inevitable (wrong turns, full garages) but it is mental energy and time that one doesnt really think of when writing out an itinerary. Just getting to Civita di Bagnoregio was slow, because of tour buses, and one way roads with slow speed limits, and limited parking and a long walk from the parking. We were able to find parking near the bridge but many other people parked a mile or more away and walked along the road.
Otherwise I think its fine. I would survey the parking at various places and have a plan so you reduce the friction of navigating as you go (for example, for Orvieto, we drove around to the 'back' and parked in a lot there - technically the West side, I believe - and did not take the funicular from the east to avoid the crowds there).

Thank you, Jessica. Would you advise skimming a day off of Rome in favor of more time in Tuscany? Maybe an extra night in Siena? We're only planning to have a car for two days, but I appreciate your advice to scout the driving route and parking in advance. I'm a big fan of making detailed plans before the trip (with some allowances, of course) to reduce decision fatigue once there!

Also, I love the idea of walking between villages in the CT and kayaking or otherwise being on the water there. Reviewing my draft itinerary, though, I'm a little afraid the entire trip we'll feel swarmed by tourists.

The idea of driving in Tuscany was to get off the beaten path a little, but is this the right way?

Should I be swapping time in the CT for Lerici? Giving up time in Rome for a longer stay in Tuscany -- maybe based in Florence, instead?

Thoughts welcome. Feeling a smidge overwhelmed.

You need to study and prioritize want you really want to see and do. There is more to each of the places you propose than you have allotted time. And yes, there will be crowds just about everywhere that will slow things down. Trains will take more time than you think to get on board, allow for schedule, etc. Driving also takes longer if only to figure out the route - e.g., Google is not good at early warning of turns. And when there is traffic near the cities, it can be a doosy. You better not get off the beaten path unless you are lost. Venice-Marco Polo airport is not that close to the Venice islands. But the train station is close by the islands. Rome-FCO is also a fair distance from the town. Plan on car drop there as driving in town is slow and easy to end up in a ZTL. Recommend accommodations nearish to Termini and take the Leonardo Express to/fro FCO. At Orvieto, free parking in a large lot near the train/bus stations and the funicular. Siena has low cost underground parking near the train station next to a mall with escalators to the town. Or take a cab up to town In both towns, you will do a lot of walking - no cars. By spending only 1 night in Siena and Orvieto, you will not have much time except an evening each. Recommend pick one. Skip Montepulciano as needs a day just to get there and back. You need to check on which CT trails are open and get reservations for some. We have been to Italy several times and have never regretted spending more time in any spot. Do not shorten your stay to save $ unless your flights are free!

If CT and seaside is important, and don't mind shorting Rome, do CT 3n, Siena 2n, Orvieto 2n, Rome 3n. One night stay is too rush for Tuscany.
If this is your first trip, replace CT with Florence (day trip to Lucca, Pisa and Siena; rent car from airport to avoid ztl, stay one Tuscany spot before returning car in Rome.

I would keep the 4 nights in CT, I think you will enjoy it and it makes it worth all the travel time from Venice. I might drop one night from Rome, and add it to Siena. I would not worry about Florence this trip, there is too much to see on its own. You could skip a car altogether. Take the train from CT to Siena, and bus and or train to Orvieto. WE did that trip in reverse, train to Chiusi from Orvieto and bus to Siena, it was pleasant and frankly you will spend as much time getting a car in Pisa, finding parking etc. Have a lovely time

Agree, you're not going to avoid crowds anywhere, even in what you think of as a "back door" location (esp. in August). The best way to have that experience anywhere is to wake up early. If you are out the door by 8am you will have an hour of quiet streets to walk. Maybe 90 minutes. I was in the CT for 3 nights, two days, with tweens and managed to hike the whole trail broken over those two days, and have plenty of water time in the afternoons. Its hard to tell you to take a night from Rome. I think 3 days for a city like that is the right number (I'd probably take a night from the CT), but you say you dont like museum-type activities, and that's a lot of what I loved about Rome, so you'll have to weigh that. If you take a night from Rome, maybe skip Civita dB, and head straight for Rome (in this case, if you do have a car you could drop it in Orvieto when you arrive there and take the train to Rome).

I was in the CT for 3 nights, two days, with tweens and managed to
hike the whole trail broken over those two days, and have plenty of
water time in the afternoons....

Worth mention is that there is no singular 'trail". The park (the CT region is a national park) is crisscrossed with many individual/interconnecting trails. The most heavily traveled route involves 4 legs (Monterosso>Vernazza>Corniglia>Manarola>Riomaggiore) which, all together, is know as the SVA2/Sentiero Azzurro (Blue Path) and involves a park pass (Cinque Terre Trekking or Treno Card) to access. The section from Corniglia to Manarola has been closed for many years now due to a rock slide; there is a workaround but is longer and more strenuous. The last leg - Manarola> Riomaggiore - is a paved path known as the Via Dell Amore. It had also been closed for a number of years due to falling rock but recently re-opened. It requires a timed-entry reservation separate from/in addition to the CT Trekking/Treno pass.

Apologies if you knew all this but it's not always understood that there's more to put boots to than the "Blue".

If you haven't found the park's website yet...
https://www.parconazionale5terre.it/Eindex.php

Map: click on any path segment for info about it (click on "View the Itinerary".) Lines in BLACK means that segment is currently closed, either short-term, as for a day due to weather, or longer term.
https://www.parconazionale5terre.it/Esentieri-outdoor.php

Info on the passes:
https://www.parconazionale5terre.it/Ecinque-terre-card.php
https://www.cinqueterre.eu.com/en/cinque-terre-card

I love the idea of walking between villages in the CT...

Also worth mention is that the SVA2 legs between Monterosso and Corniglia aren't exactly a "walk in the park" unless conditioned to vertical hiking. It involves some steep ascents/descents depending on which direction you're going, and sturdy, closed-toe shoes are a requirement. It will also be VERY busy and probably very warm.

You might consider day-tripping Porto Venere instead of Portofino? Haven't done either ourselves but over the years on this forum I've seen that one given more love by others who have. As you're also rather late at this point for making accommodation reservations in the CT, you might look at Levanto for that? It's just a couple of minutes away by rail from Monterosso, there's a nice coastal hike from that one to Monterosso as well, and it has a beach.

That hike (can do the two legs either direction, does involve some steep stairs; can take more than the 3 hours noted):
https://www.cinqueterre.eu.com/en/footpaths-cinqueterre#levanto-monterosso
https://www.parconazionale5terre.it/Eiti_dettaglio.php?id_iti=3573
https://www.parconazionale5terre.it/Eiti_dettaglio.php?id_iti=3572

I would take a day from CT and add to Siena.

Unless you are just dead set on going to the Cinque Terre (and there's nothing wrong with that), you might want to skip the CT altogether. Why? In addition to the six hour train ride, there will be time lost checking out, getting to the train station, getting to the new hotel, checking in, and etc. Basically you are losing one full on just that one relocation. Your arrival and departure days will be pretty much "lost", due to jet lag and getting ready to leave. So your fourteen days are really only evleven. If you must go to the CT, perhaps you should drop another location or shorten another stay. You want to enjoy the trip, not just endure it. Don't mean to be Debbie Downer, just offering food for thought.

Yes to what Kathy said about the "trail". To be clear, the first day we hiked from Monterosso to Vernazza, ate lunch and gelato and then continued to Corniglia and took the train back to Monteroos. The next day we took the train to Riomaggiore and ate and then hiked up and over the hill to Manarola and cliff jumped there and then took the train back to Monterosso (did not along the coast trail betwen R and Manarola, which was still closed then - so if you cant get reservations, you can hike up and over). We did not hike between Manarola and Corniglia.
Also worth mentioning: start early! We were on the trail to Vernazza by 8am. The trails were pretty well groomed iirc. I think I wore Teva's. We did hike from Rio to Man after lunch and it was HOT. If I were to do it again, I would train to Rio, and hike right away, and then eat in Manarola. Hike early, swim in the afternoon ;)

There is so much good intel here. Thank you, everyone!

Kathy, thank you for pulling the trail information together for me. I knew this was something to be investigated once I had my trip foundations set, and you just saved me so much time. I appreciate it.

I do want to keep CT on the agenda, even though the trip from Venice is long. The coast - any coast - is my family's happy place, so that's core.

I'm considering consolidating what's in-between CT and Rome per your suggestions, though, and considering shaving a day from CT or Rome to spend 2-3 nights in one spot and explore and day-trip from there. Siena or Orvieto, I'm thinking?