It depends. Mythbusters says no and in fact tested on a pair of crewcab short bed Chevys, similar to a Sport Trac. Their take was that the bed fills with high pressure air and the rest of the air flows over it.
I think a tonneau would make the most difference on a regular cab pickup.
That said, my first truck was a '99 Ranger Supercab 4x4 with a 3.0, stick, and 3.73 gears, that was so slow that it couldn't get out of its own way. After I put a tonneau on it definitely held speed on hills better.
I think a tonneau helps
tonneau cover saves gas. The little bit I know about aerodynamics tells me that your best improvement would come from a bed cap though.