Limitations of chemotherapeutic drugs for cancer treatment could be due to the lack of specificity, rapid drug metabolism, and harmful side effects. Therefore, finding new approaches in neoplastic cancer or targeting drugs depends on the pathways and characteristics of different tumor entities. Natural elements as anticancer agents are an effective strategy in the fight against cancer. This study investigated the biochemical and molecular mechanisms of Annona sp fruits extract (ASFE) in Ehrlich ascites carcinoma (EAC)-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 ASFE (200 mg/kg), Gp5 was co-treated with Cis as Gp3 and ASFE 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 ASFE 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 ASFE 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.