The skin mucus in lower vertebrates such as fish with strong innate immune system has many unique and valuable bioactive compounds that can be used for inducing apoptosis in cancer cells. This study was looking for the cytotoxic potential of mucus from the two fish species, including round goby (Neogobius melanostomus) and common carp (Cyprinus carpio), and inducing apoptosis in MCF7 and LNCaP cancer cell lines via influencing P53 gene expression and cell cycle arrest. Results showed that the both mucus types have cytotoxic effects on the both cancer cell lines whereas they have no severe effect on normal primary fibroblast cells. In addition, round goby mucus and common carp mucus selectively induced apoptosis in the LNCaP and MCF7 cells, respectively, through up-regulating P53 gene and arresting cell cycle at the G1 phase. Taken together, this study suggested that the both mucus types can selectively influence P53 pathway and induce apoptosis in especial cancer cells. The skin mucus derived from round Goby and common Carp can be a promising candidate for investigation about apoptosis and molecular targeting therapy in cancer.