US-50 is not your only option. Much of the US numbered highway system is still there, and parts of it heavily used, once you get out of the coastal areas where the Interstate system is dense enough to carry local traffic. Much of what is well traveled was upgraded in the 1980's and 1990's (the project may still be going on), doubling much of the road to four-lane divided and bypassing towns, and widening what was left to modern (12' or wider) lane widths where it is two lane.
I've covered US-60 from the Texas Panhandle to it's eastern end, and large sections of US-24, US-36, US-40, US-54, and US-66 (no longer a route on the U.S. system, since it was totally paralleled by Interstate). My US-50 experience is just eastern Kansas to Green River, and from southern Ohio into Virginia. I've also traveled sections of US-90, US-98, US-6 and US-2.
US-60 and US-50 are fairly well separated from the Interstates until you get past the Rockies.
US-40 is kind of rough to follow because a lot of it was torn up to be replaced by I-70, and where you can get off, the old highway routing is the business route through densely populated urban areas.
24, 36, 54, 66 are not coast to coast, all start somewhere west of the Atlantic Coast and not all go to the Pacific.
Another travel option, off Interstates, is to try to follow one of the national highways that preceded the numbered highway system introduced in the 1930s. One that went coast to coast was the Lincoln Highway (New York to San Francisco) while the National Road existed in the East (Cumberland to Vandalia) (mostly becoming US-40).
For guidance, many of the old highways have historical associations, and if you just want to try the mid-twentieth century numbered highways, I find "Road Trip USA" by Jamie Jensen to be a useful planning tool for these trips. The most recent edition I have (Fourth) outlines six North-South routes (four border to border or border to coast) and five East-West routes (four of those coast to coast, including US-50).