Casa Marina. We go to KW every year for Thanksgiving.

Last 150 miles are gorgeous. A lot of nice spots to see including remnants of the old train tracks and local restaurants. Another consideration is to take the ferry out of Fort Myers.

Spending a night in Ft Lauderdale or Hollywood would make a pleasant drive down through Keys next day. The drive through the keys are the best part of the trip. By stopping for one night before drive though keys will make the drive more pleasant and you could stop where you see something interesting.

fake news

Wicker House. Right off Duval towards southern end.

Fly in from Orlando !

Try to be walking distance to Duval Street. Our 2 favorite places are 'Southern Most Hotel' $$$$. And, the 'Heron House' B&B. There is so many good choices, read the reviews.

Expensive
 

We visited from a ship on a cruise, the best way to visit, and also drove on that very dangerous and horrible two lane bridge for miles & miles. We would never drive again but do the Key West Express shuttle from Fort Myers. Hotel prices were outrageous for us.

Thank you all for the suggestions.