Hematopoietic acute radiation syndrome (H-ARS) is an unmet medical requirement. Current cytokine-based countermeasures, such as granulocyte colony-stimulating factors, provide limited benefits once the surviving hematopoietic stem and progenitor cell pools are severely depleted. Toll-like receptor (TLR) agonists have been proposed as radiomitigators; however, their efficacy across ligands and receptor subtypes has not been systematically compared under equivalent conditions. Here we screened ten TLR agonists spanning eight receptor subtypes in a lethally irradiated mouse model and found that their radiomitigative efficacy was ligand-specific rather than receptor-class-specific. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and FSL-1 (TLR2/6) exerted the strongest protective effects. MPLA conferred dose-dependent survival benefits when administered after lethal total-body irradiation, and this protection was substantially abolished by myeloid differentiation primary response 88 (MyD88) inhibition and partially reduced by competitive TLR4 blockade, suggesting that the TLR4-MyD88 signaling axis contributes substantially to the radiomitigative effect. Mechanistically, MPLA did not prevent the initial radiation-induced depletion of the bone marrow (BM), but markedly accelerated the subsequent regenerative phase, restoring multilineage peripheral blood counts, splenic and BM colony-forming activity, marrow architecture, and absolute numbers of hematopoietic stem/progenitor cell populations and mesenchymal stem/stromal cells. Regeneration was accompanied by selective induction of erythropoietin and thrombopoietin in the BM without broad changes in myeloid- or lymphoid-directed cytokines. Since MPLA already has an established human safety record as a licensed vaccine adjuvant, these findings support its repurposing as a potential radiomitigator for hematopoietic acute radiation syndrome.