The use of gamma radiation in vaccine production has proven to be one of the useful methods. Nanoparticle therapy, specifically the use of ZnO nanoparticles (ZnONPs), is a promising and innovative approach to treating a variety of diseases. The study was designed to evaluate the effectiveness of irradiated tumor cell lysate vaccine and ZnONPs in treating solid Ehrlich ascites carcinoma tumors. The study monitored the tumor size, MTT cell viability, and antioxidant markers (NO and SOD) in serum. Additionally, the levels of interleukins IL-10 and IL-6 were examined, as well as TGF-β, Caspase-3, and p53 expression in tumor tissues. The results demonstrated that the co-treatment of irradiated tumor cell lysate vaccine and ZnONPs had a potent effect in reducing tumor size, TGF-β, and P53 expression, and elevating IL-6 and IL-10 levels, and Caspase-3 activity. In conclusion, the combination of irradiated tumor cell lysate vaccine and ZnONPs shows great promise as a potential cancer treatment.