Hepatic ischemia‒reperfusion (I/R) injury (HIRI) represents a frequently occurring pathological condition during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. This study intends to explore the role of B-cell translocation gene 2 (Btg2) in HIRI. We find that Btg2 expression is up-regulated following HIRI. We subsequently develop HIRl model utilizing hepatocyte-specific Btg2 transgenic over-expression and systemic Btg2 knockout male mice, discovering that Btg2 deletion mitigates hepatic inflammation and apoptosis. Furthermore, cellular experiments confirm that Btg2 knockdown alleviates inflammation and mitochondrial stress generated by hypoxia/reoxygenation (H/R) in primary hepatocytes. Metabolomics reveals that taurine metabolism is significantly impacted in the livers of Btg2-/- mice. Mechanistically, we demonstrate that Btg2 restricts the UFMylation of flavin-containing monooxygenase 1 (Fmo1), the essential enzyme for taurine synthesis, by the E3 ligase UFM1-specific ligase 1 (Ufl1), consequently facilitating the K48 ubiquitination-mediated degradation of Fmo1. Adeno-associated virus-mediated Fmo1 over-expression inhibits ferroptosis and HIRI significantly in vivo, while adenovirus-mediated Fmo1 over-expression mitigates ferroptosis and hypoxia/reoxygenation damage in vitro. Moreover, virtual screening of natural compounds reveals that Daturataturin A (DTA) inhibits Btg2 thus attenuating ferroptosis and HIRI sufficiently. These results propose that Btg2 may constitute a promising therapeutics target for HIRI.