Agricultural land use has often been linked to nutrient enrichment, habitat degradation, hydrologic alteration, and loss of biotic integrity in streams. The U.S. Geological Survey's National Water Quality Assessment Program sampled 226 stream sites located in eight agriculture‐dominated study units across the United States to investigate the geographic variability and causes of agricultural impacts on stream biotic integrity. In this analysis we used structural equation modeling (SEM) to develop a national and set of regional causal models linking agricultural land use to measured instream conditions. We then examined the direct, indirect, and total effects of agriculture on biotic integrity as it acted through multiple water quality and habitat pathways. In our nation‐wide model, cropland affected benthic communities by both altering structural habitats and by imposing water quality‐related stresses. Region‐specific modeling demonstrated that geographic context altered the relative importance of causal pathways through which agricultural activities affected stream biotic integrity. Cropland had strong negative total effects on the invertebrate community in the national, Midwest, and Western models, but a very weak effect in the Eastern Coastal Plain model. In the Western Arid and Eastern Coastal Plain study regions, cropland impacts were transmitted primarily through dissolved water quality contaminants, but in the Midwestern region, they were transmitted primarily through particulate components of water quality. Habitat effects were important in the Western Arid model, but negligible in the Midwest and Eastern Coastal Plain models. The relative effects of riparian forested wetlands also varied regionally, having positive effects on biotic integrity in the Eastern Coastal Plain and Western Arid region models, but no statistically significant effect in the Midwest. These differences in response to cropland and riparian cover suggest that best management practices and planning for the mitigation of agricultural land use impacts on stream ecosystems should be regionally focused.