The current study investigates the apoptotic effect of Baker's yeast (S. cerevisiae) on chemically-induced skin cancer in mice. Intra-tumoral treatment with yeast caused: increases in Ca2+ in skin homogenate, modulated the intrinsic/extrinsic pathways by downregulating Bcl-2 and FasL, upregulating Bax, and increased the expression of cytochrome-c and caspases 9, 8, and 3. Histopathological changes were detected, including mild dysplasia, atypia, tumor regression, and absence of basaloid cell proliferation. No toxic effects were detected, as examined by histopathological, biochemical, and body weight analysis. These results show that yeast exerts anti-skin cancer activity, suggesting its possible use for treatment of human skin cancer.