Qrvieto or Siena for car rental?

Rent from Siena, travel to Pienza, Montepulciano drop in Cortona. Spend the night. This means traveling with your luggage, so make sure it’s covered in the hatch/trunk. Or drop in Orvieto the next day (hertz only in Orvieto)

AutoEurope says they can't process an order for a pick up in Siena and a drop off in Orvieto or Chiusi. They must be out of cars?

It might be due to the fact that you are renting for one day only. AutoEurope tends to have contracts for 3 days or more. Try directly in the rental company websites (Hertz, Europcar or whatever).
If you plan to pick it up in Siena, where I think you are staying, and returning it near the locations you mentioned, Chiusi is closest to all, and they have both Europcar and Avis-Budget. Unfortunately Hertz closed the Chiusi location, but they still have it in Orvieto. If you are going to Rome after that, you might even consider the rental return in Rome.
I don't think those rental companies have offices in Cortona. The closest is probably Arezzo, slightly to the north of Cortona. If you are headed to Rome, it would be a bit of backtracking compared to Chiusi, but from Arezzo there are plenty of trains to Rome also.

Rent a car in Italy and get ready to pay huge tickets a year later.

Hey! Why do you want to scare people like that?

I've rented cars (or borrowed relatives' cars) in Italy for decades, and I never got a ticket.

A more appropriate warning is to respect the rules of the road, especially speeding, since speed limits are enforced by camera, and therefore cops aren't immediately visible if you speed.

We’ve rented and driven in Italy 3 times without getting a ticket.
Do your homework and follow the rules and you should be fine.

OP- I am wondering if the problem is the pick up/drop off time you indicated when you searched for car?
Car rental agencies close mid day, close early 12-1 on Saturday and are closed on Sunday
You might try adjusting your times after checking hours at Chiusi, Siena, Orvieto etc

AutoEurope did stop using the Hertz Orvieto location but I am pretty sure I read that had changed.

Thanks for the tips. We will look in to those times.