To evaluate the antitumor and cytotoxic activity of methanol extract of Phyllanthus polyphyllus (MPP) in mice and human cancer cell lines, the antitumor activity of MPP was evaluated against an Ehrlich ascites carcinoma (EAC) tumor model. The activity was assessed using survival time, hematological studies, lipid peroxidation (LPO), antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione S-transferase (GST), solid tumor mass, and short-term in vitro cytotoxicity. The cytotoxic activity of MPP was evaluated using human breast cancer (MCF7), colon cancer (HT29), and liver cancer (HepG2) cell lines Oral administration of MPP (200 and 300 mg/kg) increased the survival time and significantly reduced the solid tumor volume in a dose-dependent manner. Hematological parameters, protein, and packed cellular volume (PCV), which were altered by tumor inoculation, were restored. MPP significantly decreased the levels of LPO, GPx, GST, and significantly increased the levels of SOD and CAT. In a cytotoxicity study against human cancer cell lines, MPP was found to have IC50 values of 27, 42 and 38 microg/ml on MCF-7, HT-29, and HepG2 cells respectively. MPP possessed significant antitumor and cytotoxic activity on EAC and human cancer cell lines.