Groundwater-resource quality is assumed to be less responsive to drought compared to that of surface water due to relatively long transit times of recharge to drinking-supply wells. Here, we evidence dynamic perturbations in aquifer pressure dynamics during drought and subsequent recovery periods cause dramatic shifts in groundwater quality on a basin scale. We used a novel application of time-series clustering on annual nitrate anomalies at >450 public-supply wells (PSWs) across California's San Joaquin Valley during 2000–22 to group subpopulations of wells with similar water-quality responses to drought. Additionally, we statistically evaluated the direction and magnitude of multi-constituent water-quality changes across the San Joaquin Valley using a broader dataset of >3000 PSWs with data during two select hydrologic stress periods representing an extreme drought (2012–16) and subsequent recovery (2016–19). Results of time-series clustering and stress-period change analyses corroborate a predominant regional response to pumping stress characterized by increased concentrations of anthropogenic constituents (nitrate, total dissolved solids) and decreased concentrations of geogenic constituents (arsenic, fluoride), which largely reversed during recovery. Cluster analysis also identified a secondary, less commonly occurring group of PSWs where nitrate decreased during drought, but explanatory factor analysis was not able to discern hydrogeologic drivers for these two divergent response patterns. Long-term tracer data support the hypothesis that the predominant regional signal of nitrate increase during drought is caused by enhanced capture of modern-aged groundwater by PSWs during periods of pumping stress, which can drive rapid changes in water quality on seasonal and multiannual timescales. Pumping-induced migration of modern, oxic groundwater to depth during drought may affect geochemical conditions in deeper portions of regional aquifers controlling the mobility of geogenic contaminants over the long term.