If you're going to stay with the stock engine, a '50 with flathead V8 and stock gears cruising at 50-55 will do 16-18. It goes down significantly (as does engine life) if you cruise at 60-65. T-5 or OD is the way to go, I've heard many claims for 21-22 on the highway, not sure I believe it. You're pushing a barn door down the road.
Checked and rechecked my F-1 got 17.3 highway. I had a stock 302 with an Elderbrock 650 and a 2.73 rear.
Now the dream 20.
I have reworked the F-1 for a highway driver and think we may get near the 20 range, To do that we reworked a 302 with a mild roller, extensive head reworking, still using the Ellderbrock 650. A friend with a Nascar team with the software ran the numbers and we should peak at 315 horses. I added an AOD and kept the 2.73 rear and added a bed cover. Interstate sppeds should be in the range of 16-1700 rpms. We think that we may see 20 on the highway. Who knows flight testing starts the end of April, news at 11:00.
"I drive a 'girly' 302 because, when I want to go fast, I go to work"
About 10 mpg in the 54 F250 with a 460, C6, and 3.73 rear. It doesn't seem to make much difference on speed or type of driving. It would be nice to have an overdrive. I passed on a Gearvenders unit for a C6 at a swap meet (cheap) a couple of years ago. Big mistake.