I've done an awful lot of long distance driving in years past. I know what I like.
1) Room. Plenty of it. Leg room to the sides, wiggle room in the cockpit, room to place arms on a center console or armrest, without touching the person beside me. Room to put a cooler and snacks behind the drivers seat without taking up the entire back of the vehicle.
2) Tall seating position. Self explanatory. A commanding view of the road is always better. Love my S2000, but it's a horrible highway-travel car. A modern full sized pickup truck has just the right height.
3) Seat comfort. To me, that means a reasonably flat seat that fits me well, not a bucket seat. I despise the seats on certain Honda Accords. As they push on my upper back. I'm a normal sized man, with normal seating requirements. Honda got that one wrong.
4) Interior noise level, both mechanical and wind. Believe it or not, noise is extremely fatiguing. Small or cheap cars are noisy and, in the end, generally unpleasant. A good luxury car is a true pleasure on a long trip. There is a reason the Corolla is NOT a favorite for highway trips. Noisy, small and in the end, annoying.
To that end, an older Crown Vic, or better yet, a Lincoln Town Car is an ideal cheap highway car.
The one thing that never enters my mind is MPG. The modest fuel savings of high MPG always has a cost I can't bear.