Elevated nitrate concentrations in groundwater are observed in regions of intensive agriculture worldwide, threatening the safety of drinking-water production. Aquifers may contain geogenic reduced constituents, such as natural organic matter (NOM), pyrite, or biotite, facilitating aerobic respiration and denitrification. Because these electron donors are not replenished, the breakthrough of nitrate (and eventually dissolved oxygen) in production wells is only delayed. Frameworks of modeling nitrate fate and transport that assume constant rate coefficients of nitrate elimination cannot address the reduction of the aquifer’s denitrification potential by the reaction itself. We have tested several approaches of modeling the fate of dissolved oxygen and nitrate in aquifers, including multi-dimensional bioreactive transport models with dynamic abundances of aerobic and denitrifying bacteria, approaches neglecting the dynamics of biomass and dispersive mixing, and simple models based on an electron balance. We found that the primary control on the timing of nitrate breakthrough is the ratio of the bioavailable electron-donor content in the aquifer material to the electron-acceptor load in the infiltrating water. Combined spatial variability of groundwater velocities and electron-donor content can explain most of the spread in nitrate breakthrough, whereas kinetics of the reaction plays a minor role under most conditions. Our modeling study highlights the need for field surveys on joined physical and chemical heterogeneity of aquifers under the stress of pollutants that can react with the aquifer material.