Rome car rental ZTL

Well, you can certainly try. Do your homework in advance so you know where they are and how to drive around, and not through them.

I would take the train to Orvieto and pick up the car when I left Orvieto.

I would take the train to Orvieto and pick up the car when I left Orvieto.

Agreed. This would be much easier.

It is easy to avoid ZTLs in Tuscany. They are well marked and easily avoided. Anywhere within the walls of a hill town should be considered ZTL. We spent a week in Tuscany with a car and had a great time! Driving in Tuscany is easy. Just study up on the rules, don't speed (at all!) and observe the ZTL warnings.

Of course you can get out of Rome without going through the ZTL.
Tell me from which company/office you pick up the car (all companies have multiple office in Rome) and I'll tell you how.
I can also provide info on where and how safely return the car in Florence.

I use AutoEurope (a broker) to rent cars in Italy. Check all their websites for best pricing on your dates:
www.autoeurope.com
www.kemwel.com
www.autoeurope.eu
As a pick up location select ROME ALL LOCATIONS then see the best pricing.
I recommend you select the 'no deductible' insurance option for ease of mind (deductibles can be as high as 1000 euro)

If you choose to pick up in Orvieto be aware that Hertz is the only option at a local Hertz franchise office near the Orvieto station and AutoEurope no longer works with that office (I think because of poor customer service), therefore you would need to book some other way (like Hertz website).

Unless you have experience driving in Italy, you really don't want to do any driving in/around Rome if you can avoid it. As others have pointed-out, go to Orviato first, then rent the vehicle or, better yet, rent your car in Florence instead, where there's more rental companies.
As for ZTL zones, we used Waze to help us avoid those no-go and restricted areas.

@ Roberto da Firenze. Based on other comments, I would either:
1. Pick up at Orvieto and drop off at Florence at whichever drop-off location is easiest for a taxi or metro into the city, or
2. Pick up in Rome and drop off in Florence as above. In Rome, we are staying in the Monti area, so whichever pick-up location would provide the easiest route for me to pick up from and exit Rome towards Orvieta.
I suppose I could even leave the car in Siena and train to Florence if that would be even easier?
Thanks

I would agree that taking the train out of Rome then getting the rental car makes more sense, but Orvieto is down to one agency (Hertz) if that works, fine, but Chiusi, and Perugia offer more choices.

My choice would be no. 2: pick up in Rome and drop off in Florence.
Picking up in Orvieto is an option, but that would limit you to Hertz only.
Whether you would want to drop the car off in Siena or not depends on whether you willl need the car for Siena's surrounding areas or not. There are lots of nice places near Siena, or also on the way from Siena to Florence that you might be interested in visiting and that would require a car. So it's up to you.

If you are staying in Monti the closest pick up locations (for all companies) would be the Roma Termini train station (Rome's largest station), which could be walking distance from where you are. However I would search on AutoEurope and enter ROME ALL LOCATIONS as pick up points then decide. You might find out that Termini is not the cheapest deal but maybe the area near the Spanish steps (all companies have offices on Via Sardegna near the Spanish steps), in that case, although a bit farther than Termini, I would definitely take a taxi to that location and pick it up there if the savings is worthwhile. Exiting the ZTL from either location is not a problem.

For Florence the return locations are basically two:
1. downtown near the station
2. the airport, which is a bit farther coming from Siena, but easy to reach and all freeways, and no city driving, therefore no hassle. From the airport rental center then you'd need a taxi into the city center, but it's only 25 euro or so, therefore not that much more expensive than returning downtown and getting a taxi from the rental agency to the hotel (which would cost you at least 10 euro anyhow).

To return in Florence at either locations check my comments in the thread below
https://community.ricksteves.com/travel-forum/italy/dropping-rental-car-off-in-florence

Very helpful. Thank you all!