Understanding the long-term effect of nonpoint source (NPS) pollution on groundwater of agricultural regions is an increasing challenge of global importance. A novel groundwater modeling framework is developed to assess and evaluate the dynamic, spatio-temporally distributed linkages between nonpoint sources above a groundwater basin and groundwater discharges to wells, streams, or other compliance discharge surfaces (CDSs) within a groundwater basin. The modeling framework allows for efficient evaluation of NPS pollution scenarios and of their short- and long-term effects on pollutant exceedance probabilities in CDSs. Using the model, we investigate the effect of aquifer heterogeneity, well design variability, and spatio-temporal nitrate source variability on nitrate in domestic and large production wells of a semiarid, irrigated agricultural region. Results show that the timing of nitrate breakthrough in wells is significantly controlled by aquifer recharge and pumping rates in NPS areas and by the effective porosity of the aquifer system. Results further show that mixing within a domestic or large production well is a dominant source of dispersive behavior in pollutant breakthrough. In production wells with shorter screens, macrodispersivity due to aquifer heterogeneity accelerates the earliest breakthrough. Variability in well construction and spatio-temporal variability of nitrate sources most strongly control the temporal dynamics of the nitrate exceedance probability and the variability of nitrate between wells, regardless of the degree of aquifer heterogeneity. Hence, characterization of the heterogeneity of external sources and sinks is critical to understand variability and uncertainty about nonpoint source pollution in groundwater discharge locations across basins.