Struggling with Nailing Down Rental Car Pick Up/Drop Off for Tuscany

You need to pinpoint what in Tuscany you want to see, then it will be easier to select the pickup.
However, since there is a fast train to Florence (and stopping with luggage in the car is its own headache), and you will be departing to Venice from Florence, I think it would be fine to take the train from Rome, and then pick up and drop off the car rental in Florence. All you need to do is follow directions to avoid the ZTL--it is nowhere near as big a deal as some make it out to be as long as you do some basic preparation (learn the sign, know your routes, etc.). Look for some of the replies from Roberto, who has shared directions on previous posts.
Doing pickups in smaller cities might make sense if you are stopping in southern Tuscany, but given your plans I don't think you need to sweat it that much--sounds like you will end staying close to Florence anyway. Do note that the ZTL is in small villages as well as in cities--but all you need to do is know the sign and park before you enter it.

Thanks! Would you recommend just renting from a company at the Florence train station then? Not bothering with having to go to the outskirts?

I don't understand why folks think they need to train somewhere else to pick up a rental car. To me that takes longer and complicates the trip.
I would pick up the car in Rome (one of the rail stations which are easy to get to from wherever you're staying), and keep it all the way to Venice, returning it there at Santa Lucia train station (the one that's actually on the grand canal). Then use the water taxi or walk to your accommodations there.
One thing I would recommend is "zero deductible" coverage in Italy. AutoEurope shows a one way rental with this coverage, from Nov 14 - 18, $367 with the one way drop off fee. Multiple pickup locations.
Driving distance straight from Rome to Venice is 5 hours, Montepulciano to Venice 4 hours. Just to give you an idea of distance.

Don't forget you need an International Driving Permit, available from AAA in the US before you go.
Happy travels!

I have not driven out of Florence (have in Tuscany), but if I were doing the trip you are doing (looks great), that is what I would do. Just be sure to get the directions in advance and go over them. Many recommend Autoeurope for booking cars, but I have only used Hertz.

We happened to be getting off a cruise ship, so we rented within walking distance of the cruise port in Civitavecchia. I am not sure if we would have made this plan otherwise, but we stopped first in Viterbo for a couple of hours, and then in Orvieto for lunch and most of the afternoon. We arrived at our Tuscany base outside the town of Sinalunga in time for a light dinner at the hotel bar. Part of the reason we chose a rural luxury hotel was for easy in and out.

Your mileage may vary, but we parked in a public lot in Viterbo, and in the giant multi-storey mall-like car facility beside Orvieto. It went well. Note that I'm not telling you to visit these two towns, only describing one rental car solution. Don't forget to get an IDP at an AAA office. I found ZTLs to be a "big problem", although we did not get any ZTL tickets, or photo-Speeding Tickets. The problem was that my Garmin GPS tried to route me through the center of Siena (and its ZTL) to get to the recommended large perimeter parking lot recommended. The real problem, in high season, is Christmas-mall like parking conditions in the parking lots for the high-traffic towns of Tuscany.

Since the airport is in a similar direction, you could rent there, and not have to drive in downtown Rome. I think Orvieto is a good pickup idea, but make sure that the car agency is walkable from the train station, if that's how you get there. I would avoid having a car while visiting Florence, but we slept there for three nights, many years ago. Your plan to return in Florence is a good argument for renting there. But are you basing anywhere near Florence?

Given your plans, I would rent in Rome, make my way to Tuscany by car (less than 3 hr drive) and return it in Florence. If you plan to spend a day in Florence before going to Venice, then it might make sense to return it in Florence in the morning. Basically after you return the car in the morning you head to the station, drop off your bag at the luggage storage (deposito bagagli) and when you are done touring the city for the day, return to the station, retrieve your bags, and take an evening train to Venice.