First time car renters/ general advise, and 2 questions that need your opinion

Make car arrangements before leaving the US for the best deals. We never drive in Florence; it doesn't matter how good the directions, it is so easy to stray into the bus lane or ZTL. We pick up a car at the airport then drive the Chianti road towards Siena and then south to Rome where we drop at FCO and then spend a few days in Rome -- or Vice Versa pick up at FCO and drop a week or two later at the Florence airport before our time in Florence.

I don't see the point of pick up in Orvieto especially since some of the most wonderful car necessary parts of Tuscany are between FLorence and Orvieto.

I would base in a hill town in a place with parking and good access out of town. We stayed at an apartment on the wall of Montepulciano for two weeks and used that as a base; it was outstanding. I'd get a hotel for your 4 days in a historic center of a hill town with parking. The big advantage to that over a rural agriturisimo is that you can walk to a variety of nice restaurants in the evening without having to drive very dark country roads and also having to avoid drinking with dinner given the very strict drinking and driving standards. We liked having out evenings on foot but with lots of dining options. I know Montepulciano has at least one hotel with parking inside the historic center -- possibly others. I would bet that other hill towns do as well.

Be sure to catch the La Foce gardens if you are in the area on a Wednesday; you can see some of our snapshots in this area here:
https://janettravels.wordpress.com/category/tuscany/
Alas I have been lazy and didn't get things posted with photos of Montepulciano and the Abbey of St. Antimo where the monks chant daily or some of the other towns we visited.
Also be sure to visit the free hot spring waterfall of Saturnia as you drive south -- one of the most wonderful experiences we have had in Europe. No changing rooms so be prepared to dress in the open so come prepared with giant towel. I dressed by the car and managed it without problem. We did this on the spur of the moment when someone we met at an Etruscan tomb site told us about it; luckily I had a bathing suit in the car.
http://whenonearth.net/cascate-del-mulino-luxiurious-hot-spring-saturnia-italy/

Check out which will give you the best rates, keeping in mind how much the train will cost you. We rented from Florence this past June and had no issues. Just take a taxi out to the airport to pick up the car. This way you don't need to worry about ZTL's.

If you're staying in Tuscany I would keep the car for the 4 days and base out of a smaller town. This will give you the freedom to explore.

Be sure to read all the terms and conditions of the rental before booking the car. You can find these on the rental websites. They will explain charges, fees, gas services, payment types, insurances and everything else you'll need to know. Be sure to get an International Drivers Permit. They are required by law and rental companies are refusing rentals without them.

Donna

The benefit of getting a car right at the airport is the time it will save you. Since this is your first rental over there I have some suggestions:
Take some time to get GPS set up before you start driving to get you out of the airport and on to your first destination. The airport is the worst part because of all the traffic and lanes and ramps going in every direction. My setup for rental cars is a good app on my phone with a "Kenu Airframe" mount and car charger. This makes the phone easy to glance at as needed.

I also prefer to turn the sound off because with the phone mounted high right on the dash it's way easier to glance down or get help from others in the car. Often when I get through one intersection I need to immediately be in the left lane or right lane right away and the sound doesn't always clearly explain that. My app also tells me things like "take the 2nd exit at the roundabout" instead of "go straight through the roundabout" which makes way more since to me, but I understand everyone is different.

Use a consolidator to get the best deal.
www.autoeurope.com
www.kemwel.com
They are part of the same corporate group, but check prices in both sites as they differ. I've used both over the years. I like to select the no deductible insurance option (aka no insurance excess).
Picking up the car in Florence is not a problem. It is impossible to run into the ZTL while you exit the city center (cameras are only at entry points). Also the entry points are well marked and in Florence at least, signs are also in English. Bus lanes are well marked. There is a 'do not enter' sign before you enter it. There is a yellow line on the ground, it clearly says BUS on the ground, so unless people check out their brains at the rental office, you can't run into problems. Besides now virtually every historic town in Italy has a ZTL, and many of them do not have signs in English like in Florence.
The consolidators above work primarily with Avis, Europcar, Hertz.
They all have their offices in the city center on Borgo Ognissanti. If you have been scared by the ZTL terrorists on the site, then pick up outside the city center.
Europcar has another office on 2 Via Forlanini.
Hertz has another office on 53 via del Sansovino.
The above locations are far from the ZTL and near the freeway.
They all have offices at the airport, however picking up the car at the airport will cost you more because of airport rental fees.
If you return the car in Florence, select the above out of center locations, because returning the car in the city center (Borgo Ognissanti) can be tricky if you don't know Florence.
Use a taxi to go from your hotel to the pick up location of your choice.
In addition they all

Many hotels have parking, you can filter through booking.com for suggestions. I agree with having more evening options within walking distance.