a strong low-end torque engine, with an overdrive trans and good gears will get you some mpg. but there is no miracle cure. if you build the engine just right, from the ground up, you can maximize cylinder efficiency.
here's an interesting one from chevy high performance built by jeff smith, 302ci bow-tie block, crower small journal 3.00in stroke, 6.00in aftermarket rods (based on ford 6-cyl rods i believe), JE pistons (9.0:1?), and 1/16in rings. it was built at zero deck with tight clearances, afr 195 heads, with a small crane camshaft (210/220 @.050 LSA of 114) and 1.6:1 roller rockers. for induction he used a lingenfelter/ACCEL super ram and a small supercharger. it made 300hp N/A with high cylinder pressures (which greatly aids low rpm fuel mileage) with 28* of total timing and 14psi of boost he got 550hp and an average of 25mpg on the Power Tour with "...idling around on cruise nights and running down the road between 70 and 90mph!" this was in a 65 chevelle with a richmond 6-spd and 3.55:1 rear gears.
or you could get a duramax diesel and reprogram the ecm for max efficiency and/or run biofuel/waste vegetable oil. it'll swap in, not easy but it can be done.