TThis study was designed to validate the phytochemistry and the antimutagenic activity of two common plant peels; Punica granatum L. and Opuntia ficus-indica L. HPLC analysis revealed that P. granatum peels comprised mainly of 16 flavonoids and 18 phenolics; the most predominant flavonoid and phenolic were hesperidin and pyrogallol, respectively, while Opuntia ficus-indica L. composed of 18 flavonoids and 10 phenolics. The main flavonoid and phenolic compounds were kaempferol-3, 7-dirhamnoside and quinic, respectively. Compounds; α-amyrin acetate (1), friedelan-3-one (2), lup-20(29)-en-3β-ol (3), quercetin-3,4'-dimethyl ether-7-O-α-larabinofuranosyl β-D-glucopyranoside (4), punicaflavanol (5), and two hydrolyzable tannins (6&7) were isolated from P. granatum, while friedelin (8), 24-methylene-ergosta-5-en-3β-ol (9), apigenin-7-O-glucoside (10), isorhamnetin 3-O-β-D-glucopyranoside (11), and betanin (12) were isolated from O. ficus-indica. The antioxidant and cytotoxic studies revealed that P. granatum peel extract has relatively significant effects on the tested cancer cell lines, while that of O. ficus-indica peels showed potent cytotoxic activity against HCT-9 and HEPG2. The antimutagenicity study emphasized their ability to repair the genotoxic effect of the anticancer drug cyclophosphamide.