Conventional chemotherapy is an effective approach to cancer treatment. However, several side effects limited its uses. Natural products have been reported for their anticancer potential. This study evaluated the anticancer efficacy of Urtica pilulifera leaves extract (UPLE) alone or in combination with the Cis chemotherapeutic drug Cis in Ehrlich ascites carcinoma (EAC)-bearing mice. Phytochemical constituents were determined in UPLE by quantitative methods. 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 a positive control, Gp3 was injected with Cis (2 mg/kg), Gp4 was injected with UPLE (100 mg/kg), Gp5 was co-treated with Cis as Gp3 and UPLE 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 UPLE 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. Sera samples were collected for biochemical parameters assessment. Liver tissues were collected for the determination of oxidants/antioxidants biomarkers. The results showed that combinatorial treatment of the high or low doses of Cis with UPLE led to a synergistic effect on the reduction in the % b.wt changes due to the decrease in the ascitic tumor fluid. Cotreatment with Cis and UPLE exacerbates the antitumor efficacy of Cis with a significant decrease in liver dysfunctions induced by Cis and enhances the hepatic antioxidant status.