A growing interest is focused on the efficient production of deinoxanthin (DEIX) and its use as a bioactive antioxidant. Here, we produced DEIX from Deinococcus radiodurans and examined how DEIX regulates hydrogen peroxide (H₂O₂)-mediated oxidative behaviors in mouse-derived bone marrow (BM) stromal cells and BM monocytes. We also evaluated whether oral supplementation with DEIX has radioprotective potential against total body irradiation (TBI)-mediated impairments in growth, organs, survival, and hematopoietic development using a mouse model. The direct addition of DEIX recovered H₂O₂-mediated oxidative disorders in the proliferation and the balance between osteoblast and osteoclast activity of the BM-derived cells in a dose-dependent manner. We found that recovery was closely associated with the DEIX’s potencies to remove cellular reactive oxygen species and to restore the expression of key molecules that tightly control bone homeostasis. Long-term oral supplementation with DEIX (25 mg/kg body weight, once per day for 42 consecutive days) protected mice against sub-lethal TBI (5 Gy)-mediated decreases in organ and body weights and lifespan. Supplemental DEIX also inhibited TBI-mediated structural damage in organs and restored endogenous antioxidant defense systems in the liver of TBI-exposed mice. Moreover, supplemental DEIX recovered a dysregulated hematopoietic process in TBI-exposed mice. Collectively, our results introduce an efficient method to produce DEIX and demonstrate its potency to recover oxidative cellular complication in H₂O₂-exposed BM-derived cells. Overall, our findings suggest that DEIX is a great antioxidative molecule to prevent or protect TBI-mediated systemic damages.