Multiple physical and biological factors structure freshwater mussel communities in large rivers, and their distributions have been described as clumped or patchy. However, few surveys of mussel populations have been conducted over areas large enough and at resolutions fine enough to quantify spatial patterns in their distribution. We used global and local indicators of spatial autocorrelation (i.e., Moran’s I) to quantify spatial patterns of adult and juvenile (≤5 y of age) freshwater mussels across multiple scales based on survey data from 4 reaches (navigation pools 3, 5, 6, and 18) of the Upper Mississippi River, USA. Native mussel densities were sampled at a resolution of ∼300 m and across distances ranging from 21 to 37 km, making these some of the most spatially extensive surveys conducted in a large river. Patch density and the degree and scale of patchiness varied by river reach, age group, and the scale of analysis. In all 4 pools, some patches of adults overlapped patches of juveniles, suggesting spatial and temporal persistence of adequate habitat. In pools 3 and 5, patches of juveniles were found where there were few adults, suggesting recent emergence of positive structuring mechanisms. Last, in pools 3, 5, and 6, some patches of adults were found where there were few juveniles, suggesting that negative structuring mechanisms may have replaced positive ones, leading to a lack of localized recruitment. Our results suggest that: 1) the detection of patches of freshwater mussels requires a multiscaled approach, 2) insights into the spatial and temporal dynamics of structuring mechanisms can be gained by conducting independent analyses of adults and juveniles, and 3) maps of patch distributions can be used to guide restoration and management actions and identify areas where mussels are most likely to influence ecosystem function.