Cyclophosphamide and doxorubicin are often used as chemotherapy in Cancer treatment. However, these medications can cause harmful side effects, which may lead to disease progression. To address this issue, this study was conducted to evaluate the effect of combining cyclophosphamide and doxorubicin chemotherapy with low-dose gamma irradiation on the immune response and antitumor efficacy in a tumor mass animal model. Ehrlich ascites carcinoma cells (EAC) were implanted intramuscularly in the right thigh of female albino mice. The mice were then treated with doxorubicin (D) at a dose of 10 mg/kg body weight once a week for four weeks, and low-dose gamma radiation (0.25 Gy) (LDR) in the third and fourth weeks. The current study discovered that radiation might regulate angiogenesis and proliferation in solid tumors more effectively than cyclophosphamide and doxorubicin by themselves. considerable regulation of miR-21 and Let-7a fold change.Additionally, heat shock proteins 70 and 90 were decreased and the chemotherapy and radiation combination increased the apoptosis marker caspase-3. These results suggest that low-dose gamma radiation combined with doxorubicin and/or cyclophosphamide might be a useful therapeutic regimen for cancer treatment.