Although the drive is great, if you CAN fly to Key West, it could save lots of time. I live in Tampa and the drive to Key West is 8 hours. From Orlando, I would imagine it being still about 6 or 7 hours. Even at 6 hours, if you only have minimal time to spend, try to fly. It's only about an hour or so to fly and once in Key West, you don't need a rental car. Try to stay near Duval Street as that is where most of the fun is. Hemmingway's House, Southernmost Point in US, Sloppy Joe's and Captain Tony's, and everything tourist related as it is also nearby the dock for the Cruise Ships. All within Crawling, err... Walking distance.
HAVE FUN