My standard route (from Boston area) would be I-90 to I-84 to I-81 to I-77 to I-26 to I-95, and then in Florida A1A to US-301 to I-75 at Ocala.
For variety, I sometimes go I-81 all the way to I-40 to I-75, but this means going through or around Atlanta, which is sometimes not too bad...and sometimes a character building experience.
Another not unreasonable option, though somewhat slower going, is to make your way to the Garden State Parkway and then take the Cape May ferry and Chesapeake Bay bridge/tunnel and head on down e.g. US17 until it intersects I-95. That gives the opportunity to stop at a variety of interesting coastal places, such as Assateague and Cape Hatteras, and avoids the worst of city driving.