The brief discussion below is copied from the American Great Loop Cruisers’ Association forum. Really, there are at least three different routes from Marathon to Cape Sable and the Western Florida coastline (or the other way around), but the first message below refers to only the easternmost of the three, known as the Yachtsman’s Channel.
In the second message below, our good friend, Captain Chuck Baier, gives some good general advice about this passage!

This is actually the reverse of what you want to do but it gives you some perspective. There is a place called Yachtsman’s Channel which is accessible from Channel 5 which is well north of Marathon. In fact you could take the ICW all the way to Yachtsman.
From that channel you pass by Cape Sable and which is the edge of the gulf.
Name Not Provided

We have made that crossing several times. About the best advise I can give you is to wait for the weather. You don’t have any information that I can find on the type of boat you have, the draft or how fast you can travel so the question is hard to answer. Ideally you want to wait until any fronts forecast on the way are already through and the seas have settled down. You can wait at Indian Key or Shark River to be a little closer. If you have a slower trawler you will want 24 hours of wind and or seas NOT on the beam and 10 knots or less winds. We use 24 hour wind and wave reports from weatherfax rather than NOAA vhf forecasts to make our decision. Best advise I can think of is to not try and outrun any approaching fronts.
Chuck