Camshaft has ALOT to do with the entire performance and fuel economy successes or failures of an engine. It's also about where in the rpm range the engine makes the numbers vs the rpm where the cruise speeds are at. Once again, that is another area where camshaft will make you or break you. Fuel vaporization is also an INSANELY huge factor in both the performance and mileage successes or failures an engine. If the system does a poor job of fuel vaporization, it will waste alot of gas.
This is an area where a spread bore carburetor will reign superior over a square bore. Airflow is pointless without great vaporization characteristics, as air does not burn without fuel vapor.
Don't over pipe the exhaust system in terms of diameter.
Don't be the least bit afraid of a 289/302 as a baseline. Be afraid of the wrong combination.
In general, yes. If you have a straight 6 engine you might get OK gas mileage. Any v8 will get relatively poor MPG. The bigger the engine the worse MPG you'll get. All Mustangs were carbureted until the mid 80's so they're not as efficient or clean running as they are today.
"Waste" is an odd term for you to be using here. You're driving it to get somewhere or to enjoy the experience of a classic car so you're not really wasting anything.
If you're thinking about buying one as a daily driver then forget it. At about 10 MPG combined city/highway at worst with a 428CJ v8 and about 20 at best with a 250 straight 6 you will be paying a lot every week to drive it every day. Nowadays, the car is meant as a weekend car and for occasional pleasure driving. Back in the 70's that was alright gas mileage but not today at $3.50-$3.75 a gallon.
They don't "waste" gas as such, they just use a lot of it! Don't expect far into double figures for mpg, but that's not a "waste" as you get a lot of power, and it's a big car. I get about 16mpg from my car, but I don't consider it a "waste" as it's high performance, and a heavy and luxurious car.
The thermo efficiency of the older engines is not as good a new ones, but still pretty close. It is not that they waste a lot of gas, it is just that it takes more fuel to move that much car. But if the driver is gentle on the gas and drives to conserve fuel they can do pretty good.