Responses in the vadose zone and groundwater to interannual, interdecadal, and multidecadal climate variability have important implications for groundwater resource sustainability, yet they are poorly documented and not well understood in most aquifers of the USA. This investigation systematically examines the role of interannual to multidecadal climate variability on groundwater levels, deep infiltration (3–23 m) events, and downward displacement (>1 m) of chloride and nitrate reservoirs in thick (15–50 m) vadose zones across the regionally extensive High Plains aquifer. Such vadose zone responses are unexpected across much of the aquifer given a priori that unsaturated total-potential profiles indicate upward water movement from the water table toward the root zone, mean annual potential evapotranspiration exceeds mean annual precipitation, and millennia-scale evapoconcentration results in substantial vadose zone chloride and nitrate reservoirs. Using singular spectrum analysis (SSA) to reconstruct precipitation and groundwater level time-series components, variability was identified in all time series as partially coincident with known climate cycles, such as the Pacific Decadal Oscillation (PDO) (10–25 yr) and the El Niño/Southern Oscillation (ENSO) (2–6 yr). Using these lag-correlated hydrologic time series, a new method is demonstrated to estimate climate-varying unsaturated water flux. The results suggest the importance of interannual to interdecadal climate variability on water-flux estimation in thick vadose zones and provide better understanding of the climate-induced transients responsible for the observed deep infiltration and chemical-mobilization events. Based on these results, we discuss implications for climate-related sustainability of the High Plains aquifer.