Background: Semecarpus anacardium Linn. is a commonly used Ayurvedic medicinal plant. Their different parts including nuts, have various medicinal properties to treat clinical ailments such as vitiligo, inflamation, microbial infection, geriatric problem, baldness and neuro-related problems.Aim of the study: The main objective of this study was an evaluation of the anticancer activity of the leaves of Semecarpus anacardium Linn and phytochemical screening. Materials and methods: The phytochemical screening was carried out through GC-MS analysis. Cytotoxicity was examined using MTT assay whereas mode of cell death evaluated by fluorescence microscopy. Finally, antitumor activity was determined in EAC cell-induced tumorbearing mice. Results: The ethyl acetate extract induced cytotoxicity in cancer cells in a dose dependent manner (IC 50 : 0.57 µg/ml in MCF-7 cells) in different cancer cell lines. However, normal cells were relatively insensitive to the extract. Fluorescence microscopy results, confirmed that the extract induced apoptosis in cancer cells effectively. The extract induce cell cycle arrest at the G1 phase and suppressed cancer cell migration. An oral administration of the extract suppressed the tumor growth in the mice model bearing Ehrlich ascites carcinoma cells. Whereas, the ethyl acetate extract was also found to prolong the survival of tumor-bearing mice. Conclusion: Overall, these observations suggest the anticancer activities of the ethyl acetate extract of S. anacardium leaves. The study opens a new window to examine the phytochemical constituents from the leaves as a source for the anticancer compounds.