Quantifying changes in the cover of river-floodplain systems can provide important insights into the processes that structure these landscapes as well as the potential consequences to the ecosystem services they provide. We examined net changes in 13 different aquatic and floodplain land cover classes using photo interpreted maps of the navigable portions of the Upper Mississippi River (UMR, above the confluence with the Ohio River) and Illinois River from 1989 to 2000 and from 2000 to 2010. We detected net decreases in vegetated aquatic area in nearly all river reaches from 1989 to 2000. The only river reaches that experienced a subsequent recovery of vegetated aquatic area from 2000 to 2010 were located in the northern portion of the UMR (above navigation pool 14) and two reaches in the Illinois River. Changes on the floodplain were dominated by urban development, which increased in nearly every river reach studied from 1989 to 2000. Agricultural lands declined in most river reaches from 2000 to 2010. The loss of agricultural land cover in the northern UMR was accompanied by increases in forest cover, whereas in the lower UMR and Illinois River, declines in agriculture were accompanied by increases in forest and shallow marsh communities. The changes in aquatic vegetation occupied between 5 and 20% of the total aquatic area and are likely associated with previously reported regional improvements in water clarity, while smaller (1–15% of the total floodplain area) changes in anthropogenic land cover types on the floodplain are likely driven by broad-scale socio-economic conditions.