The rising interest in innovative methods of cancer immunotherapy has prompted research into the immunomodulatory mechanisms of natural and synthetic substances. The goal of this study was to assess chrysin immune-stimulating and pro-apoptotic effects on tumor growth and cell susceptibility to ionizing radiation in order to improve cancer therapy. Chrysin (20 mg/kg/day) was intraperitoneally injected to mice bearing 1 cm solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole body exposed to 1 Gy of gamma radiation (2 fractionated dose 0.5 Gy each). Treatment with chrysin dramatically reduces tumor proliferation in EAC mice; furthermore, IFN-γ activity is significantly reduced when compared to EAC mice. When compared to EAC mice, the expression of TNF-α, free radicals, and nitric oxide (NO) levels were considerably reduced, along with improvements in apoptotic regulators (caspase-3 activity). Moreover, the histopathological investigation confirms the improvement exerted by chrysin even in the EAC mice group or the EAC + R group. What is more, exposure to gamma radiation sustained the modulatory effect of chrysin on tumor when compared with EAC + Ch mice. Hence, chrysin might represent a potential therapeutic strategy for increasing the radiation response of solid tumor.