The entire circuit around the Great Lakes (that includes the area you mentioned) is well worth the time and effort. We took our boys one summer when they were 8 and 10. It took us a week, factoring in time to stop and explore, but was well worth it for all four of us.
It’s not - Independence Pass closes for the winter.
Agreed - it’s a beautiful drive and I try to do it at least once a year.
(From cotrip.org): Each year, the two-lane, 12,095-foot pass closes for the winter for the safety of the travelling public and CDOT maintenance crews. The closure typically occurs on or near November 7 and the highway is almost always re-opened on the Thursday prior to Memorial Day each May. Please check www.cotrip.org as the pass will be posted under “Alerts and Restrictions” if it is closed to travel.
Oh… and I came here to mention the Million Dollar Highway (Ouray CO), Going to the Sun Road, and Beartooth Pass in MT/WY and they’ve already been done.
I’ll add Trail Ridge Road, the road from one side of Rocky Mountain National Park, CO to the other. It’s the highest paved through-road in the USA.
For sheer sphincter-challenging, end-of-the-cliff driving, you can drive up Pikes Peak to 14,110’ elevation. It’s not quite as exciting since they paved it.
The section of A1A that runs between Palm Coast and St. Augustine is also quite lovely. I drive from Orlando to Jacksonville for work quite frequently and I’ll take a 20-minute detour from I-95 to drive it on a pretty day.
Route 201 from Fairfield to Jackman, Maine. The terrain is varied, and there’s a good chance you’ll see moose or deer. You follow the Kennebec River for almost the entirety of the trip. It’s the only place I’ve been that has rumble strips in the road to alert you to the presence of this sign. Driving through some of those towns is like going backwards in time.
There’s also a dirt road up north called the Golden Road. It goes from the Canadian Border to Millinocket. It’ll take about five or six hours to travel the whole length of it. Moose sightings are almost guaranteed. When last I was there, you had to pay per passenger for access, since it was a private road. I don’t know if that is still the case now that the Millinocket paper mill is out of business. You’ll want at least eight-ply tires for this one, else you risk having multiple flats in the middle of nowhere, many miles away from help.
The Mooshead Trail from Belfast to Moosehead Lake as well. You’ll see many quaint rural towns of Maine along the way. I never tire of driving through Plymouth Pond on that road.
A lot of people fail to realize that there is so much more to Maine than the coast.
I like the Niagara River Parkway that stretches from Niagara-on-the-Lake to Niagara Falls, Ontario. Short but vey scenic.
Get a sober friend to drive (by offering to pay all expenses for a day out), and go with some friends - hit the various wineries along the way, stop to look out over the Niagara river gorge from time to time. We did that, and it was an awesome way to spend a summer day. 
I’ll nominate Highway 14A from Spearfish to Deadwood in the Black Hills of South Dakota. Then you can take Highway 385 from Deadwood to Hot Springs for another scenic foray.
Driving what was then US 666 (and apparently is now US 461) from Gallup to Shiprock, N.M. was one of the most interesting drives this never-lived-outside-of-the-EST guy has ever done. Desert, spectacular rock formations, the endless sky. Next day was even more spectacular: US 160 from Teec Nos Pos, Arizona to US 191, through Many Farms and Ganado, then Arizona 264 to Window Rock.
I stopped for gas at a trading post in Teec Nos Pos, and said “Yah te hey” to the guy behind the counter. He looked at me like I was an idiot; it only just now occurred to me that he might not even have been Navajo.
Texas FM170 from Presidio to Study Butte (the river road).
Window Rock, Arizona to the North Rim of the Grand Canyon via Tuba City.
I-80 from Wendover to Salt Lake City in the middle of the night with a full moon.
Good call, and this is what I came in to post. It’s a long drive from Thunder Bay to Sault Ste. Marie, but a very scenic one.