I don't know if any route off the Interstate is more relaxing, if it is not more leisurely. And if more leisurely, it is going to add more time. What tends to make Interstate driving more exhausting for me is trying to maintain a hectic pace to get "there" as quickly as possible. I doesn't have to be that way.
We've been going Detroit to Florida (and back) for Christmas since my grandfather moved in 1950 to his Depression-era ranch in central Florida. As more relatives moved to Florida, we picked up more destinations, and eventually we ended up in Orlando and were driving the other direction for vacations. Have thus been making the trip for many years, constantly altering the routes as more of the Interstate system got built.
Before I-75 was built, the Detroit-Brooksville trip was four days, or three very long days, on the most direct routes, about 1200 miles. You can still follow some of those routes, but most were so closely paralleled by I-75 that you'll be routed on the Interstate much of the time if you try to follow the route numbers.
I-75 going as far as southern Georgia cut the Detroit-Brooksville trip down to two very long days, 1150 miles, overnight in Chattanooga. I have siblings, cousins, nephews and nieces who just make it one very long day, about 22 hours driving, 24-25 hours with breaks. That's for destinations between Ocala and Brooksville, so Port Charlotte will be another 100-150 miles, 2-3 hours. That's exhausting. We've also done it as three days, stops in central Kentucky and Georgia, that's more relaxing.
Our last Florida trip before my wife died, we chose a leisurely route, visiting places along the way. We dropped my brother off at Detroit Metro morning of December 27th, met him at his home in Beverly Hills January 4th. That was 1800 miles through the Virginias to the Atlantic Coast, then down the coast into Florida. That was about four days of driving, four days of sight-seeing, and a lot of it was still done on Interstate highways: I-75 to the Ohio River, I-64 to cross the mountains and get to Hampton Roads, I-95 from Savannah into northeast Florida. The driving on those sections of Interstate was much more relaxed than it had been using, forty years earlier, the two-lane highways they replaced.
I now make 6-10 trips a year between Michigan and Oklahoma-Kansas, part of it on Interstates, part of it on other roads (occasionally even county roads), choosing the less busy Interstates and avoiding as many urban areas as possible (suburban traffic is probably the worst I encounter on the system). As a two day trip, the 1000 miles is exhausting. As a three or four day trip, short days and sightseeing, it is relaxing and fun. So it is not the road, it is the pace.
I suggest a leisurely route, pick some places you want to see along the way, take a week or two going down. Going to Florida in November, if you choose to follow the coast, you should be out of "winter" weather once you cross the Appalachians. Instead of ice and snow, bad weather will more likely be just gray or maybe wet. The year we did it, West Virginia was mostly clear of snow along I-64, between Christmas and the New Year, and the whole trip down the coast was in sunshine.
