I start at the state level for those I might pass through, see what the tourism department is proud of. My wife used to send off for the brochures and tour books, and we collected them at state welcome centers and local visitor centers. Right now I still have three file drawers worth of stuff for the Deep South, Midwest and Southwest.
Most of the information is now online for the state level at least, but we always found going over the hard copy stuff together was more convenient to planning discussions.
Two years at Myrtle Beach, with home in Michigan, in the era before most of the Interstate highways east of or through the Appalachians we made six trips to or from the Great Lakes region and never went the same way twice. First was in the dead of winter, we were in snow and ice from Rocky Mount to Conway, so we didn't see much of anything, not even other cars. Being from Michigan, it didn't occur to us that people in the South didn't drive on ice-covered roads. After retirement, we made the trip again (in winter) through SC enroute to Florida.
Rest of the trips were summer, each one started with just a broad plan "we want to see this part of the country" and we stopped when we found something interesting. Interstates make this harder, since they bypass everything except major metro areas, so you have to know where stuff is to get off the highway and find it.
Keep in mind that there are many useful routes, not much difference in distance and cost, time doesn't matter when not in a hurry. You can go up the eastern coastal plain as far as Maryland or Pennsylvania and go east from there to the Lake Erie area. If thinking about Chicago, Wisconsin, Minnesota, you can cross over to Atlanta then go north through Nashville, or all the way to Memphis through Alabama and Mississippi, and north from there. To Michigan, up I-75 through Tennessee, Kentucky and Ohio to the Lake Huron side of the state, or up through Nashville, Louisville and Indiana to the Lake Michigan side (or Chicago and on into Wisconsin).
Other places to cross the Appalachians include the Smokies, Ashville to Knoxville, the Cumberland Gap, and western Virginia into central West Virginia and southern Ohio Amish country. Interesting north-south sections include sections of the Blue Ridge Parkway or following the Shenadoah valley. A lot of it is cosidering what you've already seen, or what might fit into another trip you plan to make.
35 years I've regularly traveled NE Oklahoma to SW or SE Michigan, have had about a dozen regular route combinations and regularly deviate from those in small ways to see places I've never seen before, even while going through others I want to frequently revisit.
Going into a new area, I also check the library for travel stories in addition to travel guides, and my own library includes 2-3 dozen travel books (mostly gifts from relatives) used for planning and dreaming. National Geographic, Reader's Digest, Discovery Channel's Insight Guides, Frommer's have been the most useful major publishers, but some of the best for local areas are small regional publishers.