Ecosystem processes in rivers are thought to be controlled more by extrinsic than intrinsic factors, that is, the result of processes that occur upstream or within their watersheds. However, large floodplain rivers have a diverse assemblage of aquatic areas spanning gradients of connectivity with the main channel and internal controls may at times regulate long-term dynamics. When and where internal controls are important has not been widely explored in rivers. The Upper Mississippi River System (UMRS) provides a unique opportunity to assess regulation of ecosystem processes in a large floodplain river as water clarity has increased in several reaches over the last two decades. To better understand when and where intrinsic variables (for example, aquatic vegetation and common carp) and extrinsic variables (for example, upstream main channel total suspended solids (TSS) concentration and discharge) regulate water clarity, we describe 24-year trends of TSS in six study reaches of the UMRS. We evaluated the degree to which trends were shared across aquatic areas within each study reach and identified potential drivers of long-term TSS dynamics. Results varied across and within UMRS reaches, but common carp abundance was the strongest predictor in nearly all study reaches. Several models indicated associations with both intrinsic and extrinsic factors, and the marginal model r² values (0.26–0.61) suggest that additional environmental factors may have influenced water clarity. Knowledge of the degree to which intrinsic and extrinsic processes regulate water clarity is important for understanding and managing large, floodplain rivers worldwide.