Aquatic vegetation is a key component of large floodplain river ecosystems. In the Upper Mississippi River System (UMRS), there is a long-standing interest in restoring aquatic vegetation in areas where it has declined or disappeared. To better understand what constrains vegetation distribution in large river ecosystems and inform ongoing efforts to restore submersed aquatic vegetation (SAV), we delineated areas in ~1200 river km of the UMRS where the combined effects of water clarity, water level fluctuation, and bathymetry appeared suitable for establishment and persistence of SAV based on a 22-year dataset for total suspended solids (TSS), water surface elevation, and aquatic vegetation distribution. We found a large increase in suitable area downstream from a large natural riverine lake near the northern end of the UMRS (river km 1230) that functions as a sink for suspended material. Downstream from river km 895, there was much less suitable area due to decreased water clarity from tributary input of suspended material, changes in river geomorphology, and increased water level fluctuation. A hypothetical scenario of 75% reduction in TSS resulted in only minor increases in suitable area in the southern portion of the UMRS, indicating limitations by water level fluctuation and/or bathymetry (i.e., limited shallow area). These results improve our understanding of the structure and function of large river systems by illustrating how water clarity, fluctuations in water level, and river geomorphology interact to create complex spatial patterns in habitat suitability for aquatic species and may help to identify locations most and least likely to benefit from management and restoration efforts.