Chemotherapeutic drugs for cancer treatment cause several side effects. Natural-derived constituents as anticancer agents are effective against various cancer types. This study addressed the synergistic effect of the co-treatment with avenanthramides (AVNS) and cisplatin (Cis) in Ehrlich ascites carcinoma-bearing mice. Seventy mice were divided into seven groups (n = 10) as follows: Gp1 was used as a negative control, from Gp2 to Gp7 were inoculated with 1 × 10⁶ EAC-cells/mouse, then Gp2 left as EAC-bearing mice, Gp3 was injected with Cis (2 mg/kg), Gp4 was injected with AVNS (50 ng/kg), Gp5 was co-treated with Cis as Gp3 and AVNS as Gp4. Gp6 was injected with a low dose of Cis (0.5 mg/kg), and Gp7 was co-treated with a low dose of Cis as Gp6 and AVNS as Gp4. The body weight change percentages (b.wt%) were calculated. On day 14, all groups were sacrificed, the ascitic fluids were harvested, and the total tumor volume, count, and live and dead tumor cells were measured. The relative expression of P53, Bcl-2, BAX, and caspase-9 genes was determined in EAC-cells by RT-PCR. Sera samples were collected for biochemical parameters assessment. Liver tissues were collected for the determination of oxidants/antioxidants biomarkers. The results showed that co-treatment of the high or low doses of Cis with AVNS led to synergistic effects via targeting apoptosis in EAC-cells that can significantly inhibit tumor growth, decrease liver dysfunctions induced by Cis, and enhance the hepatic antioxidant status.