Hydrogen sulfide (H2S) is an endogenously produced gaseous second messenger capable of mitigates pathological cardiac remodeling by regulating several cellular processes including fibrosis, hypertrophy, apoptosis, and inflammation. This study was dedicated to determine the cardio-protective efficacy of hydrogen sulfide alone or in combination with L-carnitine, co-enzyme Q10 or alpha lipoic acid against cardiovascular disease occurred as a result of γ-irradiation in male albino rats. The obtained results revealed a remarkable change in all studied parameters after exposure to γ-radiation. However, irradiated rats treated by H2S showed a significant (p<0.05) decrease in the activities of serum cardiac enzymes (CK, CK-MB, LDH & AST) and in the concentration of heart fatty acid binding protein (H-FABP) and endothelin-1 as well as the levels of cytokines profile (IL-1β, IL-10 & TNF-α) associated with a remarkable decrease in the level of heart TBARS than those in irradiated rats. On the other hand, H2S caused a significant (p<0.05) increase in the level of TNO, heart GSH content and GPx activity than those of irradiated rats. Additive of L-carnitine or Co-Q10 to H2S produced considerable improvement in all studied parameters, which become more pronounced in case of L-carnitine but less in case of Co-Q10 while, the addition of α-lipoic acid did not induce any noticeable changes. It is concluded that the use of L-carnitine increase efficacy of H2S and could exhibit modulatory effects on γ-radiation-induced cardiovascular disease in rats.