Greater Horn of Africa (GHA) is projected to face negative impacts on per capita food production due to dwindling nature of water resources forced by climate change and rising population growth. The region has limited groundwater irrigated agriculture and also lacks groundwater monitoring infrastructure. This study (i) employs Independent Component Analysis (ICA) to localize Gravity Recovery and Climate Experiment (GRACE)-derived groundwater changes and analyses the corresponding temporal variabilities and their link to climate indices (Indian Ocean Dipole (IOD) and El Niño-Southern Oscillation (ENSO)), and (ii), explores the irrigation potentials of the localized groundwater. Monthly GRACE-derived groundwater changes showed similar temporal variability to WaterGap Hydrological Model (WGHM), i.e., a correlation of 0.7 (significant at 95% confidence level), highlighting GRACE's potential to provide GHA-wide changes in groundwater. Based on GHA aquifer location maps, the study associated the localized groundwater changes to nine major aquifers namely; Nubian sandstone, Karoo Carbonate, Upper Nile, Ethiopian highlands, Lake Tana region, Kenya-Somalia, Central Tanzania, Karoo sandstone, and Ruvuma. All temporal groundwater changes, except Nubian sandstone and Kenya-Somalia, showed an annual (cyclic) pattern indicating an annual (yearly) recharge cycle. Weak relationships with rainfall and both climate indices were noted. Maximum correlation occurred when rainfall preceded the temporal groundwater changes by several months. Based on water availability (from GRACE), water quality (indicated by the total dissolved substance) and dominant soil types, potential for groundwater irrigated agriculture results showed: low potentials for Nubian Sandstone and Kenya-Somalia areas; low to moderate potentials for Karoo Carbonate, Lake Tana region, central Tanzania, and Ruvuma; moderate to high potentials for Upper Nile and Karoo Sandstone; and high potential for Ethiopian highland. Even though the study has considered relatively short time period (10 years), these results are critical to the sustainable management of the region's groundwater resources and appropriate/informed policy formulation.