By chance, this is "Drive the Great River Road Month" and there is a $500 sweepstakes on the website.
https://experiencemississippiriver.com/the-great-river-road-the-best-drive-in-america/I've driven bits and pieces of it. Wished we knew which direction you are going (N or S). Headed north, at the southern tip of Illinois, cross the river either on the I-57 bridge or the old US 62 bridge (one of the oldest on the river, very high and has 10 ft wide lanes. Turn off on Illinois highway 3 and head north.
Most of the road is on the valley floor and you have bluffs on one side, and farm fields, RR tracks and the river on the other. You will encounter a number of historic markers. nothing real big or important. I didn't find much to see or do at Cape Girardeau, but the fairly new bridge is kinda neat. Continuing north, you eventually come to Chester, the home of Segar, the creater of Popeye. At the east side approach to the bridge you will find a small museum and information center, both about the bridge, and the town and Popeye. A drive thru town, including going inside the Hardees, it worth it as there are murals and statues of the Popeye characters all over town.
Going North out of Chester either take county 6 from the bridge approach, or take state 3 and turn left on county 3. Both take you to the river, at the Ft Kaskaskia Historic Site. There is a nice campground there.
https://www2.illinois.gov/dnrhistoric/Experience/Sites/Southwest/Pages/Fort-Kaskaskia.aspxContinue north on state 3 to and thru Ellis Grove, and turn left on Roots Road and cross the Kaskaskia River. If you are looking for a camping spot, turn left after crossing the river and drive to the dam, where there is a Corp of Engineer campground. If you don't need a place to stay just continue after crossing the river on the Bluff road and it takes you to Modoc and Prairie De Rocher. This is very scenic as the towns are set under the edge of the bluffs. If you have a desire to cross to the Missouri side, Modoc is the last place to do this before St Louis, as there is a ferry that crosses. Some of these roads are dirt/gravel but are quite smooth and easy to drive on, just dusty. The ferry can handle semi trucks so an RV should not be a problem.
http://stegenmodocferry.com/I purposely try to cross the big Muddy every different way I can, just to say I have. This could be expensive for you, I would call first and verify what they will charge, I crossed in a car back in 2012.
Skipping to north of St Louis, Hannibal is a must stop (Mark Twain boyhood home) and all the towns are rather scenic. If you are a military history buff, the museum at the Rock Island Arsenal is well worth the side trip. Do this in your car, this is a government installation and you have to sign in and out. There is a Confederate POW cemetery there, and a display of field artillery and tanks a couple of blocks from the museum. Gate guards will give you directions.
US 67 on the Iowa side, just north of the I-80 bridge is Le Clair, the birth place of Buffalo Bill Cody, and there is a neat city museum there next to the river. Up toward Princeton are signs taking you off to the Boyhood home of Buffalo Bill. Nice county operated museum. Not far, but a zig zag road trip is the Scott county Park which has nice RV camping.
Make your way back to the river at Clinton. On the Iowa side is a eagle watching park north of town and if you cross over to Fulton there is a real Dutch windmill on the Levee and a museum nearby. In Fulton just north of the windmill is a cemetery on a very steep bluff side and the parents of Ronald Reagan and other family members are buried there.
**The drive north from Clinton on the Iowa side is very scenic, (never drove the Illinois side north of Fulton to Savannah) and at Sabula Iowa, take the toad across the oldest bridge on the Mississippi (1929) to Savannah. The bridge is size and weight restricted and I don't think a MH is allowed.
North of Sabula/Savannah, at Blanding ILL, and Bellevue Iowa, are a number COE camping areas right on the river.
Jumping further north, I highly suggest driving Wisconsin highway 35 from Prairie de Chien north to La Crosse. Extremely scenic drive under the bluffs.
There is a river aquarium at Dubuque, and about 30 miles west of Dubuque on US 30 at Dyersville is the National Farm Toy Museum (worth a couple of hours) and not far away is the "Field of Dreams".
Charles
** Confusing to say the least. Fulton, Ill claims that 16 of Reagan's relatives are buried in Calvary Cemetery in Fulton (including his parents?) however, other information shows that Ronald Reagan's parents are buried in Calvary Cemetery in Los Angeles California.