I agree also. Consider the difference between driving during the day on a clear road and driving at night or during a big rainstorm or snowstorm. Driving 300 miles in the clear is a lot less tiring than driving 50 in the snow.
True. The same with sitting watching movies. The wife and I will often go catch two in one day at the cinema, but we never do three because we’re too tired after that.
I’ve just come off a 150 mile drive which incorporated a mountain range and a 15 mile tailback on that range. When I got to the bottom and the outskirts of the city, the tailback delay made me hit the right time of evening for the boy racers all along the suburban freeway. So I’ve arrived home a bit tired and grumpy.
But not too tired. There have been times - and this is why I’m quoting your post - when I’ve done 400+ mile drives, and I’ve actually decided to combat fatigue by driving more aggressively. I certainly don’t mean driving like an arsehole when saying this, but I mean I’ll aim for slicker gear changes, I’ll line up corners precisely, I’ll even drive a bit faster (again, not speeding, but using the fast lane where I’d otherwise be content to use the slow one) and otherwise become more involved in my driving. It’s no substitute for a nap, but I do find it makes me drive more rather than less safely.
For me, the tiredness is due to concentration. I’m constantly scanning the road ahead for potential disasters; my dad is a truck driver (a really, really good one) and he taught me to always be alert and ready for the unexpected.
That and the bag of black Twizzlers.
Dehydration is a biggie.
My Dad was a traveling salesman, & always brought bottled water with him.
He swears it helped.
I also find I’m way less tired when I’m driving with cruise control turned out. That I’ve assumed has to do with some fatigue associated with continued pressure on the gas pedal that has to be “just so”.
Driving a car is relaxing for me. How much effort does it take to watch the road? Like Lobsang, I also find it like meditation. Paying attention to the road is not tiring - my brain sort of runs on autopilot until it sees something interesting / dangerous.
A few weeks ago I drove 2400 miles in two days. It was one of the highlights of my summer. I was less tired at the end of both days than I normally am in the evenings.
I find it helps to speed. If you’re going faster than everyone else, you know exactly where everyone is - behind you, and receding rapidly. 
I read somewhere that driving, especially on the interstate system, induces “highway hypnosis,” and to overcome that the brain has to work extra-hard to focus on keeping the two-ton machine hurtling down the road at 70+ mph on that road. I also saw on TV (Discovery Channel, I think) that the reason humans are omnivores is because the human brain requires huge amounts of calories to make the millions of calculations it makes all day long. Those two facts, plus the fact that even if you’re sleeping “on the road” (I did this a lot in Germany when I was in the Army) you don’t sleep well because of the constant influx of stimuli (jostling from vehicle movement, etc.) tell me that our brains get a real workout while traveling, and that’s what makes us tired. 'Course, I[m not a brain scientist, but that’s what I’ve read/heard on the topic.
Why Is Driving a Car So Tiring?
Because you don’t walk ten miles everyday.
Nobody has mentioned passengers. My children bickering in the back are the most tiring aspect of driving; not to mention my husband’s ineptitude at map-reading and inability to stop criticizing (even though he can’t drive).
Accumulated stress over blowing a gasket every time you see a cyclist?
You’re doing it wrong.
Lack of physical exertion is exhausting whether driving, watching a movie, sitting in the park. Doing nothing is so tiring because there is little opportunity to stop and rest.
We actually talked about this at a meeting at work. Like some others have said, part of the fatigue is from all these little muscles in your body that help you balance have to work constantly.
Being that I drive for 8 hours a day, 5 days a week for a living, I know very well this tired feeling that is described. Stretches, and physical activity definitely help. When I have breaks, if I’m not hungry/need to go to the bathroom, I tend to walk around for as long as possible. Sometimes when I’m tired I lie down in the back seats of the bus just to give those muscles a break for a few minutes. It helps.
This all reminds me of when they dropped the speed limit down to 55mph in the US. A big argument against it was that it was slow enough to seem boring and impart a false sense of safety but still fast enough to kill you. I guess faster speeds are not enough in themselves to keep you alert after all.