Is it worth it to rent a car for the day- Tirano to Florence?

Personally? I would still opt for the train. First, it is quicker, about four and a half hours by car, an hour less by train, not including the time to get from the Florence Airport to where you are going, some fast trains may shave off two hours. Second, a seat in a modern train is much more comfortable than shoehorning into the smaller cars that seem to be available, unless you were planning on moving up to a Mercedes or BMW, and you can reasonably stretch your legs on the train.

Further, while driving, to see some things, is appealing to the road trippers in us, given the time you arrive in Turin, then get the car, plan for time to drop the car and then get to your hotel in Florence at a reasonable time to get settled, likely does not leave much more than the four and a half hours you need for driving, maybe a bathroom break, but no long lunch at a winery, or wandering some off the beaten path, quaint village.

If you start comparing cost, the car may wind up cheaper, but as you implied, it likely will take two with 6 adults and luggage, plus consider fuel, tolls, insurance, and some factor for risk of speeding or ZTL violations.

I don't know if you are going to find any car rental spots in Tirano, it is a small town.

Are you going to Florence or the Florence airport? And if the airport, why go all the way to Florence?

I took the Glacier Express one day and the Bernina Express the next. The landscape is so amazing that I didn't get tired of it.

I also vote for the train if going to Florence.

Definitely take the train. It only requires one step-free connection in Milano Centrale, and the train is about 2x as fast as driving for the Milano-Florence section. Much easier to stretch one's legs on a train, too!
And in any case, I doubt you'd find a rental car in Tirano. I'm only finding repair shops/car dealers, who aren't set up for one-way rentals across the country.

Thank you all for your thoughtful, considered input. It's really helpful!

Sitting in a train is much more comfortable for everyone, especially the would-be driver.

Thank you all for your replies. You've really helped us come to a decision.

I'm a little late into this thread and it seems you have decided on the train.
Personally, I'd drive. We have an 18 day (2000 mile) western Europe road trip coming up in April (if the mask insanity is relaxed.)
My wife and I are true road trippers. When we road trip we are always looking for new and unusual things. When passing a side road we may go down it just to see what's there. We do stop a lot and that takes up time so you can't be rushed or need to get some where in a hurry. All six in your party need to agree if you decide to drive otherwise it will be miserable for everyone.
Whatever you decide, have fun.

Thank you- if we had more time, I'd be very tempted to drive.