The present study was premeditated to examine the radioprotective effects of aqueous Aloe vera gel extract against whole-body X-ray irradiation–induced hematological alterations and splenic tissue injury in mice. Healthy male balb/c mice were divided into four groups: group 1, control; group 2, A. vera (50 mg/kg body weight) administered per oral on alternate days for 30 days (15 times); group 3, X-ray exposure of 2 Gy (0.25 Gy twice a day for four consecutive days in the last week of the experimental protocol); and group 4, A. vera + X-ray. X-ray exposure caused alterations in histoarchitecture of spleen along with enhanced clastogenic damage as assessed by micronucleus formation and apoptotic index. Irradiation caused an elevation in proinflammatory cytokines like tumor necrosis factor and interleukin-6, total leucocyte counts, neutrophil counts and decreased platelet counts along with unaltered red blood cell counts and hemoglobin. Irradiation also caused an elevation in reactive oxygen species (ROS), lipid peroxidation (LPO) levels, lactate dehydrogenase activity and alterations in enzymatic and nonenzymatic antioxidant defense mechanism in plasma and spleen. However, administration of A. vera gel extract ameliorated X-ray irradiation–induced elevation in ROS/LPO levels, histopathological and clastogenic damage. It also modulated biochemical indices, inflammatory markers, and hematological parameters. These results collectively indicated that the A. vera gel extract offers protection against whole-body X-ray exposure by virtue of its antioxidant, anti-inflammatory and anti-apoptotic potential.