My view....
1. Make sure you're rigged for true offshore running. This means EPIRB, raft, and other suitable gear. Appalachicola -> Clearwater takes you 60nm offshore and that's the shortest in both distance and time in terms of offshore transit. It is also unavoidable as there is no ditch path all the way there. Steinhatchee is a viable if long abort but if you get caught and have to use it you've already screwed up.
2. If you're going go to do Appalachicola -> Clearwater, go up the ditch at least from Pensacola to Appalachicola. You can run for most of it and IMHO it's worth it, unless you have truly outstanding weather. If you do, well, outside is nice too, shadowing the beach. There are a few notable slow zones on this path - near the Brooks Bridge in Ft. Walton is one; another is near the Bay in Panama City where there are a lot of residential docks in a very narrow ICW, and a few places between Appalachicola and Panama City. But for most of it, you can get up and run and it's protected water. Just be aware that there is a fair bit of commercial barge traffic on that waterway - use your head! If you stop in or around Destin or Ft. Walton let me know and I'll come have a drink with 'ya.
3. If you're willing to go slow and have the weather window, direct either Mobile, Pensacola or Destin -> Clearwater is a good choice. You need crew for this so you can maintain a proper watch. At displacement speeds your fuel goes a LOT further. In terms of DAYS this will be faster, but it's "all at once." It will also be a LOT cheaper fuel-wise. If you don't have the crew for it then it's dangerous; likewise if you try to push it on the weather window. Don't attempt this without knowing you have the fuel range for it with a 30% reserve at the speed you're going to make the run.
4. As noted there are often other vessels making the transit in either direction; those going southbound typically will be at Appalachicola if they get socked in weather-wise. When we brought Gigabite home we were part of convoy of about a dozen that left Clearwater. Half turned around and bugged out within the first hour or so, another half reduced to displacement speeds. IMHO the latter is folly - either make the run or, if you find the conditions too sporty for you and your vessel, turn around. Running unfamiliar inlets at night is IMHO a fool's game.
I've made this run a number of times in both directions, including when bringing Gigabite home (I live on Choctahatchee Bay, so Destin is my "home port".) With good weather conditions it's a nice run. With bad WX it's anything from miserable to dangerous. Note that the so-called "wave forecasts" are frequently wrong and while stated in feet, they are often really in METERS. Know where your bugout point (where you can return) is and where you're committed to continue. Running out of fuel 20nm short of land sucks.