You will save time and money renting from the downtown location. In Italy airport locations typically charge a premium so money savings for that plus the cost to get yourself to the airport cost.
I did not think driving out was bad, driving back in probably more challenging and I did not do that, not sure if your plans require you to or not.
We rented from the Europcar office in downtown Florence, address is Via Borgognissanti, 53/55/r, 50123 Firenze, Italy
There is a Hertz rental place on the same block.
The booking was through Auto Europe and from that location the drive out of town post checkout was not difficult, just make sure to ask for directions out and follow them. You really would have to backtrack or turn around to run into a ZTL as they are monitoring cars entering not leaving if that makes sense.
I think you received good advise by the comment that it depends on your comfort with urban driving in the US.
Florence driving seems much more tame than Rome or Naples.
And you really are going to drive down one very easy side street ; you will get your car on Via Borgognissanti, headed left the direction away from town ; follow that road ; a very easy to drive not crowded side street with a few stop signs until the road ends.
Then at the end of the road be funneled to your right with no option of turning the wrong way onto a city highway (the road ends and you are forced to go right) which loops around the city ;
At this point you are now outside of the main ZTL so don't want to enter inside the walled area of town again
you will have to exit off of this mini loop highway to get onto another highway out of town once you do that any city driving is over.
I would definitely do that again and glad we did not rent from the airport location which I had considered for all of the same reasons you are.