I've seen 60's Corvette's with 375 HP 327's get close to 20 mpg on a trip,provided the driver refrained from using the secondaries ...the engines then had up to 11:1 compression,some had a bit more!,that is the key to greatest efficiency,the higher the compression the more power you get out of every drop of fuel....of course we had gas back then that could run an engine with that compression--todays engines are lucky to have 9:1 compression,and the computer and fuel inhection helps make up for the loss of efficiency...imagine what we could get from a higher conmpressioin engine with todays technology...
Cams also determine how good an engine will be on fuel,there are cams specially ground for better fuel economy,and often engines with one not only get better gas mileage,but also see a profound increase in low end torque and driveability,and outperform an engine with a "hot" cam in street driving .....I've had big blocks get better mpg than small blocks I've owned too,a smaller engine dont always mean it'll be a fuel sipper...a big engine loafs along at a fast idle to propel a 3 ton truck,while a 305 will struggle to get one moving and use more gas doing it....you can get away with gearing a tad too "high" with a big block,that would smother a smaller engine,and that will gibe better fuel economy..
I would say 15 mpg in a full sized truck with a properly built engine should be attainable...the size of the carb is critical too--too many people plop on a 750 CFM double pumper and wonder why it wont run good or get over 8 mpg--when a much smaller carb would be much more efficient ,possibly even increase power too...
I had a friend with a 455 Olds with a 2 bbl that got 17 mpg ,in a ;68 Delmont 88,a big tugboat,that had 10,75 :1 compression..the 2 barrel was far superior to the 4 barrel Holley he swapped on it with a 4 bbl intake...he lost 5 mpg and it never ran as well,so he ditched it and put the stock 2 bbl back on it...I had a 450 CFM Holley Economaster on a '74 454 and I got 16 mpg a few times on my 75 mile commute with it...you can get some impressive MPG if you learn not to give it more than 1/4 throttle--floor it once though,and you'll watch the gas gauge drop!..