In this study, we explored the protective effects of oyster (Ostrea plicatula Gmelin) polysaccharides (OPS) against genotoxicity and liver injury induced by cyclophosphamide (CP) in BALB/c mice. OPS was administered to mice at doses of 100 and 200mg/kg for 7 consecutive days, then 50mg/kg CP was injected via abdomen. Then mice were sacrificed and samples were collected. Bone marrow micronuclei (MN) and polychromatic erythrocytes (PCE): normochromatic erythrocytes (NCE) ratio were calculated to evaluate CP induced genetic toxicity. Activites of transaminase and antioxidants in serum as well as liver histopathology were examined to assess the severity of liver damage. We further investigate the molecular mechanism by Western blot analysis. When CP induced group pretreated with OPS, the generation of MN was obviously reduced accompanying by the restoration of PCE: NCE ratio. We also found that pretreatment of mice with OPS markedly reduced the release of serum alanine transaminase (ALT) and aspartate transferase (AST). Histological examination and grading evaluation also showed that OPS could significantly attenuated CP-induced liver damage. At the same time, OPS supplementation attenuated CP-induced oxidative stress as evident by the alternation of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. Furthermore, CP induced mice showed the downregulation of Nrf2 (nuclear factor E2 – related factor 2) – ARE (antioxidant response element) and the downstream genes i.e. NAD(P)H: quinine oxidoreductase-1 (NQO – 1) and Hemoxygenase-1 (HO – 1), which were obviously reversed by OPS pretreatment. In conclusion, OPS protects against the genotoxicity and hepatotoxicity induced by CP in vivo. The beneficial effect may depend on activation of Nrf2 – ARE pathway and subsequent suppression of oxidative stress and genetic toxicity.