Depending on the time of day you're driving, about 4-4 1/2 hours. It's a pretty easy drive until you hit Broward/Dade area, then it's usually smooth sailing.
Avoid rush hour at all costs!
I would budget about 4-5 hours. The ride isn't so bad until you exit the mainland of Florida and hit the keys. While they are interesting to see, a world all their own, it's not highway driving. It's one lane (SOMETIMES two) in and out. So all it takes is one accident and you are stopped completely. I have driven to Key West from Fort Lauderdale area and had it take 3 and a half hours and I have also had it take nearly 5 hours, so it varies a lot! If you haven't been there, it's really worth the drive!
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