Pyroptosis is characterized as gasdermin-mediated programmed death and has received substantial attention in recent years. Excessive hepatocyte pyroptosis could induce acute liver injury, and there is a lack of efficient natural compounds to alleviate it. Ginsenoside Rb1 is the most prevalent ginsenoside in ginseng with a variety of biological activities and is usually added to functional foods. In spite of the numerous beneficial effects ginsenoside Rb1 exerts, its role in hepatocyte pyroptosis is yet unknown. In this study, we found that ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, which is critical for the process of pyroptosis. Furthermore, with the addition of the mitophagy inhibitor cyclosporin A, we proved that ginsenoside Rb1 promoted PINK1/Parkin-mediated mitophagy to alleviate hepatocyte pyroptosis. The further mechanism was that ginsenoside Rb1 activated mitophagy to eliminate damaged mitochondria. With the clearance of damaged mitochondria, reactive oxygen species production decreased, and then NLRP3 inflammasome expression was inhibited. Our finding demonstrated that ginsenoside Rb1 could alleviate hepatocyte pyroptosis by activating mitophagy, which could provide a basis for formulating effective dietary therapy or dietary recommendation.