Context: Ulva lactuca Linnaeus (Chlorophyceae), a commonly distributed seaweed, is rich in polysaccharide but has not been studied extensively.Objective: The present study investigated the effects of crude fraction of Ulva lactuca polysaccharide (ULP) on D-galactosamine (D-Gal)-induced DNA damage, hepatic oxidative stress, and necrosis in rats. Materials and methods: The rats were treated with ULP (100 mg/kg, orally) for 4 weeks before a single intraperitoneal injection of D-Gal (500 mg/kg). In addition to liver cell necrosis and DNA damage, antioxidant parameters, such as lipid peroxide (LPO), superoxide dismutase, and catalase, and histopathology of liver tissue were evaluated. Results: ULP pre-treatment significantly attenuated a D-Gal-induced decrease in DNA and RNA levels (3.67 AE 0.38) and (5.42 AE 0.46), respectively. Comet tail length and acridine staining confirmed the number of cells undergoing necrosis were relatively lower in ULP treated rats (30 mm and 8-10% of counted cells) compared to rats treated with D-Gal (60 mm and 16% of counted cells). Biochemical (LPO, SOD and CAT) and histological evaluation (p50.01) confirmed the anti-hepatotoxic and antioxidant property of crude polysaccharide against D-Gal-induced elevation of LPO and infiltration of inflammatory cells into liver tissue. Discussion and conclusion: Although our previous studies have reported on the protective role of ULP against liver toxicity, our present findings show that ULP improved the hepatic antioxidant defense system against D-Gal-induced DNA damage and necrosis in rats.