Irrigation has enhanced food security and biofuel production throughout the world. However, the sustainability of irrigation faces challenges from climate variability and extremes, increasing consumption from irrigated cropland expansion, and competing demands from other water use sectors. In this study, we investigated the agricultural water withdrawal landscape of the contiguous US (CONUS) over 1981-2015, assessed its spatial and temporal changes and analyzed the factors driving the changes. We introduced the concept of “center of mass” to calculate the spatiotemporal trajectory of water withdrawal, along with climatic and agricultural factors at state, regional and CONUS scales. At the CONUS level, the total agricultural water withdrawal has been decreased during 1981-2015, and the centroid of water withdrawal consistently shifts toward the east, caused by reduced water withdrawal in western states and increased withdrawal in the eastern states. While the CONUS irrigation trajectory is resilient to climate variability, prolonged regional drought may interrupt the trend. In the Western US, irrigation withdrawal reduction is mainly achieved by adoption of high-efficiency irrigation technology. Under drought conditions, irrigation withdrawal often switched from surface water to groundwater sources, posing challenges on groundwater sustainability under prolonged droughts. The Eastern US has experienced accelerating agricultural withdrawal from both surface water and groundwater sources. This is mainly driven by increased irrigated acreage in the Midwest and lower Mississippi River, with irrigated croplands supplied by mixed flood irrigation and high-efficiency irrigation methods. At the state level, some states exhibit discrepancy in agricultural withdrawal centroids from surface water and groundwater sources, as results of climate heterogeneity, water availability and infrastructure development. This study provides understanding of the driving forces in the spatiotemporal trends of CONUS agricultural water withdrawal in different regions and implications for predicting future agricultural withdrawal under changing climatic and socioeconomic uncertainties.