From Chicago, take I-55 south to Springfield, and then take I-72 west. I-72 crosses the Mississippi River on substantial modern bridge, with great views of the river. The west bank of the River is a high mound or ridge that looks down upon the town of Hannibal. I-72 then ends and becomes US 36. US36 is now a modern divided highway that crosses the entire state of Missouri. So, it provides an excellent relaxed but efficient alternative route to the much busier cross continental I-80 to the north or I-70, which links directly between the metropolises of St Louis and Kansas City. From St Louis, take US 61 north; this is a somewhat scenic rural route, but without views of the Mississippi River. If you are driving a motorhome, be careful about driving through historic downtown Hannibal. Parking down there is limited, especially right at the waterfront, but there are spaces here and there given the generally relaxed small town feel of this Missouri hamlet. Unfortunately, the railroad tracks cut Hannibal off from the waterfront.
They have these trolleys, or trailers, or whatever they call them, that you can board and they will take you around town.