Water scarcity is a critical issue in semiarid regions; however, regional groundwater monitoring is extremely limited. This study evaluates the ability of the GRACE satellites to monitor groundwater storage in the semiarid High Plains aquifer, United States (450,000 km2 area), which is subjected to intense irrigation. GRACE-derived terrestrial water storage (TWS) is highly correlated with the sum of soil moisture (SM) and groundwater storage (GWS) (R = 0.96 for in situ measured SM from 78 stations and R = 0.95 for simulated SM with the Noah land surface model with root-mean-square difference of 38 mm and 36 mm, respectively). Correlation between seasonal GWS changes calculated from GRACE TWS minus SM and measured GWS (∼1000 wells per season) is also high (R = 0.73 for in situ SM and R = 0.72 for simulated SM). Variability in SM is mostly restricted to the upper 2 m of the soil. Monitored SM compared favorably with simulated SM (R = 0.82). Study results show the potential for using GRACE gravity measurements to monitor TWS and GWS over large semiarid regions subjected to intense irrigation.