Run lots of timing and lean primary jetting.
I get 19-20mpg highway in my '78 t/a. st-10 4 speed, 3.23 gears, 6x-8 headed 400, 744 cam, quadrajet on a Torker 1 intake, 1 5/8" 4 tubes through 2.5" dual exhaust. I run 38 total timing (gives best mph in 1/4) all in by 2400rpm with full manifold vacuum. At 2700rpm cruise (or around 70mph with 255/60/15 tires) I have over 50 degrees of timing and I barely have to press the gas to maintain speed. My carb has stock (lean) primary jetting with the secondary metering rods changed to give best mph in 1/4 (around .050" tip size, maybe CE rods? can't remember). This probably doesn't result in the best mixture distribution, but with the open plenum of the T1 it's probably decent under higher rpm WOT, which is all I really care about. I'm not running enough compression for the lean jetting or timing to cause any sort of heat/detonation problems, so probably get better mileage than what a 9.5 or 10:1 engine would be capable of using pump gas, and can do so on 87 octane.
If you're running an auto with a non-lockup torque converter, even with overdrive I'd say you'd be doing good to get 16-17mpg. With an o/d manual trans (or 2.73 gears) you could see 21-22mpg. Auto with lockup t/c and o/d could probably get similar 19-20mpg as my non o/d manual.
Keep in mind a 4.21" stroke engine will have more internal friction and therefore be less efficient than a 3.75" stroke engine. Probably a 1-2mpg difference even with lower gearing proportional to the displacement increase.
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