Stream fish distributions are hypothesized to be strongly associated with landscape characteristics at multiple scales. Variation in flow regimes and intensity of landscape disturbance is associated with stream fish distributions; however, relationships are poorly understood in many high-diversity regions. Our objective was to identify occurrence relationships between fish distributions and streamflow and landscape characteristics in the south-central United States. Our study area was the central Red River catchment in Oklahoma, Texas, and Arkansas, USA. We used existing fish surveys to model the occurrence of a diverse, warmwater assemblage among hydraulic response units (HRUs). We used multispecies occupancy modeling to identify variation in occurrence probability among 111 stream fishes in relation to landscape disturbance and flow regime characteristics. We found significant occurrence relationships with landscape disturbance and 11 metrics comprising all flow regime components. The relationships varied within both major species groups and some genera. Frequency and duration were the most common flow regime relationships. More common stream fishes tended to be positively associated with higher levels of landscape disturbance and flow regime metrics representing variability. Conversely, less-tolerant, narrow-ranged fishes tended to be negatively associated. Occurrence relationships with flow metrics representing high-flow events were predominately negative. As expected, many species were strongly associated with and ecoregion with landscape disturbance and flow relationships held constant. Our study informs land-use and water management decisions and stream fish conservation at multiple spatial scales. Collectively, the findings suggest potential homogenization of the Red River fish assemblage with increased landscape disturbance and streamflow variability. A reduction in landscape disturbance and maintenance of natural flow patterns at coarser scales may benefit endemic and narrow-ranged fishes. Our findings also guide finer-scale land-use and water management decisions by identifying stream network areas with a high occurrence probability of less-tolerant fishes.