The biguanide metformin is widely used for the treatment of Type-II diabetes. Its antiproliferative and pro-apoptotic effects in various tumor cells suggest its potential candidacy for cancer chemoprevention. Herein, we report that metformin significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which was associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. This tumor growth reduction was accompanied by the enhanced apoptotic cell death and an increase in Bax:Bcl2 ratio. The mechanism by which metformin manifests antitumor effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Decreased phosphorylation of NFkB inhibitory protein IKBα together with reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 were observed. In addition, a decrease in the activation of ERK/p38-driven MAP kinase signaling was seen. Similarly, AKT signaling activation as assessed by the diminished phosphorylation at Ser473 with a concomitant decrease in mTOR signaling pathway was also noted as phosphorylation of mTOR regulatory proteins p70S6K and 4E-BP-1 was significantly reduced. Consistently, decreased phosphorylation of GSK3β, which is carried out by AKT kinases was also observed. These results suggest that metformin blocks SCC growth by dampening NFkB and mTOR signaling pathways. © 2012 Wiley Periodicals, Inc.