This study aimed to investigate the prophylactic effect of selenium-enriched Cordyceps militaris (CS) against triptolide-induced acute hepatotoxicity. Rats were intragastrically administrated with CS and ordinary Cordyceps militaris (CM) for 7 consecutive days prior to triptolide intoxication. Triptolide elevated levels of serum aminotransferases, total cholesterol and caused severe liver injury. However, CS remarkably inhibited the increases of these parameters and pathological damages. The action mechanisms might be associated with its antioxidant property by enhancing antioxidant enzymes activities and triggering nuclear factor E2-related factor 2 (Nrf2) translocation and downstream genes expression. Besides, CS prevented cellular apoptosis through up-regulating Bcl-2/Bax ratio and down-regulating cytochrome c and caspase-3 cleavage. Constituent analyses showed that CS had higher amounts of cordycepin, selenium, selenocystine and polysaccharides than CM. In conclusion, CS effectively prevented triptolide-induced hepatotoxicity via activating Nrf2 pathway and inhibiting hepatocyte apoptosis, suggesting that it could be a promising hepatic protector and a befitting nutraceutical supplement.