Despite the ubiquitous existence of dams within riverscapes, much of our knowledge about dams and their environmental effects remains context-specific. Hydrology, more than any other environmental variable, has been studied in great detail with regard to dam regulation. While much progress has been made in generalizing the hydrologic effects of regulation by large dams, many aspects of hydrology show site-specific fidelity to dam operations, small dams (including diversions), and regional hydrologic regimes. A statistical modeling framework is presented as a predictive tool to quantify and generalize hydrologic responses to varying degrees of dam regulation at large spatial scales. In addition, the approach provides a method to expand sample sizes beyond that of traditional dam-hydrologic-effect analyses. Model performance was relatively poor with models explaining 10–31% of the variation in hydrologic responses. However, models had relatively high accuracies (61–89%) in classifying the direction of hydrologic responses as negative or positive. Responses of many hydrologic indices to dam regulation were highly dependent upon regional hydrology, the purpose of the dam, and the presence of diversion dams. In addition, models revealed opposite effects of dam regulation in systems regulated by individual dams versus many upstream dams, suggesting that the effects of dams may be countered by other dams in basins experiencing intensified cumulative disturbance. Results also suggested that particular contexts, including multipurpose dams, high cumulative regulation, diversions, and regions of unpredictable hydrology are all sources of increased error when predicting hydrologic responses to dams. Statistical models, such as the ones presented herein, show promise in their ability to generalize the directionality of hydrologic responses to dam regulation and provide parameter coefficients to inform future site-specific modeling efforts.