The High Plains aquifer (HPA) is the primary water source for agricultural irrigation in the US Great Plains. The water levels in many locations of the aquifer have declined steadily over the past several decades because the rate of water withdrawals exceeds recharge, which has been a serious concern to the water resources management in the region. We evaluated temporal trends and variations in agricultural water use and hydroclimatic variables including precipitation, air temperature, reference evapotranspiration, runoff, groundwater level, and terrestrial water storage across the HPA region for different periods from 1985 to 2020 at the grid, county, or region scale. The results showed that water withdrawals decreased from 21.3 km³/year in 1985 to 18.2 km³/year in 2015, while irrigated croplands increased from 71,928 km² in 1985 to 78,464 km² in 2015 in the entire HPA. The hydroclimatic time-series showed wetting trends in most of the northern HPA, but drying and warming trends in the southern region from 1985 to 2020. The groundwater level time-series indicated flat trends in the north, but significant declining in the central and southern HPA. Trends in irrigation water withdrawals and irrigation area across the HPA were controlled by the advancement of irrigation systems and technologies and the management of sustainable water use, but also were affected by dynamical changes in the hydroclimatic conditions.