Surface water storage in small yet abundant landscape depressions-including wetlands and other small waterbodies-is largely disregarded in conventional hydrologic modeling practices. No quantitative evidence exists of how their exclusion may lead to potentially inaccurate model projections and understanding of hydrologic dynamics across the world's major river basins. To fill this knowledge gap, we developed the first-ever major river basin-scale modeling approach integrating surface depressions and focusing on the 450,000-km2 Upper Mississippi River Basin (UMRB) in the United States. We applied a novel topography-based algorithm to estimate areas and volumes of ~455,000 surface depressions (>1 ha) across the UMRB (in addition to lakes and reservoirs) and subsequently aggregated their effects per subbasin. Compared to a "no depression" conventional model, our depression-integrated model (a) improved streamflow simulation accuracy with increasing upstream abundance of depression storage, (b) significantly altered the spatial patterns and magnitudes of water yields across 315,000 km2 (70%) of the basin area, and (c) provided realistic spatial distributions of rootzone wetness conditions corresponding to satellite-based data. Results further suggest that storage capacity (i.e., volume) alone does not fully explain depressions' cumulative effects on landscape hydrologic responses. Local (i.e., subbasin level) climatic and geophysical drivers and downstream flowpath-regulating structures (e.g., reservoirs and dams) influence the extent to which depression storage volume in a subbasin causes hydrologic effects. With these new insights, our study supports the integration of surface depression storage and thereby catalyzes a reassessment of current hydrological modeling and management practices for basin-scale studies.