ME3738 is a new compound that attenuates liver disease in several models of acute and chronic liver inflammation. We used the concanavalin A (Con A) model to elucidate the molecular mechanismsof ME3738 to block liver cell damage. Pretreatment of BALB/c mice with ME3738 prior to Con A injection resulted in a significant reduction in liver injury. The protective effect of ME3738 prior to Con A injection was associated with a reduction in IL‐6 serum levels and NF‐κB DNA binding in liver nuclear extracts. However, STAT3 DNA binding was induced via ME3738 prior to Con A injection. Further analysis showed that ME3738 induces IL‐6 serum levels and activates STAT3 DNA binding and target gene transcription. The relevance of this finding was assessed in IL‐6^–/– mice. Inthese animals, ME3738 induced no increase in IL‐6 serum expression, and activation of IL‐6‐dependent pathways was not found. In addition, ME3738 did not protect IL‐6^–/– animals from Con A‐induced liver failure, while IL‐6 injection was still effective. Therefore, we demonstrate that ME3738 triggers IL‐6 expression, which activates pathways that are relevant to protect from Con A‐induced liver failure.