AbstractAmanita phalloides species mushrooms containing alpha‐amanitin (α‐AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α‐AMA‐induced hepatotoxicity. We investigated the effects of resveratrol on α‐AMA‐induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α‐AMA (α‐AMA + SR) or 12 (α‐AMA + 12R) or 24 (α‐AMA + 24R) hr after α‐AMA administration. Silibinin (5 mg/kg) (α‐AMA + Sil) and normal saline (α‐AMA + NS) were given simultaneously with α‐AMA. We found that liver transaminase levels in α‐AMA + SR and α‐AMA + 12R groups and histomorphologic injury score in the α‐AMA + SR, α‐AMA + 12R, α‐AMA + 24R and α‐AMA + Sil groups were significantly lower than that of the α‐AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase‐3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by α‐AMA in THLE‐2 and THLE‐3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by α‐AMA + NS. As a conclusion, resveratrol was found to be effective in α‐AMA‐induced hepatotoxicity with its anti‐inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.