It can really wear you out. When I was younger, I worked out a standard MO:
Never more than three hours at a stretch; two is better. I would estimate travel times from Google Maps and break it into 2- and 3-hour blocks. Lunch and dinner were obvious extended break times, but I always took a break -- not just a trip to the restroom, but a get-out-and-walk-around, stretch-my-legs, get-some-fresh-air break of 15 min or so. Made travel times a bit longer, but very much worth it. Depending on when meal times were, I would do the longest stretch as either the first or final leg -- never the last for really long trips, though, to minimize the effects of fatigue. When you're getting off the Interstate and merging into local traffic, you don't want to be too tired and lose alertness.
Oh, and I had chemical help -- a big sugary chocolate bar, followed by a Diet Coke and Red Bull (this was before the better flavors came out), usually past the halfway point. I kept meals modest -- a full stomach can lead to drowsiness.
Always carry aspirin, and something stronger, especially for eyestrain headaches. Vanquish or generic equivalent were the strongest I ever used.
I managed to survive more than ten years of that -- often driving rental trucks with all my belongings -- but hope that if I ever have to do that again, it will be to a take a position with my very last employer, and never have to relocate again. I count myself lucky I almost never had an accident on such trips (oh wait -- I did total my car on one long commute), especially in a moving truck, or a breakdown in the middle of nowhere. Came close to both, including one time when I thought the truck would overturn ("uneven lanes" sign should have been posted BEFORE the off-ramp, dolts!).
All part of the price of not finding extended employment anywhere. Commutes included south GA (near the FL border) to OH every two weeks, and WV to western MA every week. All living and driving alone most of the time. Just the kind of thing I thought I could avoid by spending years in grad school to get a PhD. Just doesn't seem to work in this country anymore.