The radioprotective efficacy of a methanol extract of the red algae Polyopes lancifolia (Harvey) kawaguchi et wang (mPL) was evaluated in mice subjected to total-body gamma irradiation. mPL protection against radiation-induced oxidative stress was examined by histological evaluation of intestinal crypt-cell survival and liver activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). mPL (100 mg/kg body weight) administered intraperitoneally at 24 h and 1 h prior to irradiation protected jejunal crypt cells from radiation-induced apoptosis (p < 0.01). The pretreatment of mPL attenuated a radiation-induced decrease in villous height (p < 0.05), and improved jejunal crypt survival (p < 0.05). The dose reduction factor was 1.14 at 3.5 days after irradiation. Treatment with mPL prior to irradiation resulted in significantly higher (p < 0.01) levels of SOD and CAT activities, compared to those levels of irradiated control mice with vehicle treatment. These results suggest that mPL is a useful radioprotective agent capable of defending intestinal progenitor cells against total-body irradiation, at least in part through mPL antioxidative activity.