I can answer that one because we live right here. Up the Mississippi, then the Missouri at St. Louis, and then you can go as far up as Sioux City, Iowa (well, a few miles beyond but not much more). And the current rips really badly around Sioux City. Above Sioux City the river gets shallow and thready and marshy with lots of sandbars and deltas. They do a canoe and kayak run some years between Sioux City and Yankton, but the days of the riverboat steamers are long gone between Sioux City and Yankton. We have a 19' Bayliner runabout and I've wanted to try the Yankton to Sioux City run, but most advice I've ever gotten is don't risk your boat.
And then around Yankton the river opens up again, beautiful boating and beautiful areas, but then you hit the first of a series of dams in Yankton. Our marina is just above the first dam, Gavins Point, Lewis and Clark. The river is huge above that all the way to Montana, but you'd have to hop multiple dams, and there are no locks. Our five year plan is to have the boat shipped to Duluth and we sail out into world from the Great Lakes. We could ship it to Sioux City instead, or Omaha, but if we have to ship the boat anyway, might as well do Lake Superior.
So in short, for a boat of any size, as a practical matter, Sioux City, Iowa.