We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha leaf extracts (petroleum ether, benzene, chloroform, ethyl acetate, methanol, and water extracts) on 6 human cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) and normal (IMR-90, HEK-293) cell lines. Of all the extracts tested, chloroform and ethyl acetate extracts of M piperita showed significant dose- and time-dependent anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, acquisition of senescence phenotype, while inducing pro-inflammatory cytokines response. Our results provide the first evidence of direct anticarcinogenic activity of Mentha leaf extracts. Further, bioassay-directed isolation of the active constituents might provide basis for mechanistic and translational studies for designing novel anticancer drugs to be used alone or as adjuvant for prevention of tumor progression and/or treatment of human malignancies.