Background <p>Polystyrene microplastic (polystyrene) has emerged as a prevalent environmental contaminant that exerts significant hepatic injury. The current work explored the mitigating capability of galangin against polystyrene-evoked hepatotoxicity and unveiled the potential associating molecular pathways.</p> Methods and results <p>Male Wistar rats (<i>n</i> = 40 in total) were subjected to polystyrene with or without concomitant administration of galangin. Hepatic function, tissue architecture, and key molecular signaling pathways were evaluated using ELISA, histopathological examinations, and Western blotting techniques. Galangin co-administration was associated with mitigation of hepatic dysfunction and tissue damage, as evidenced by a significant decrease of serum bilirubin and amelioration of the histopathological alterations. Additionally, hepatic inflammation was reduced, as indicated by modulation of the inflammatory cytokines. Moreover, hepatocellular apoptosis and oxidative stress were suppressed. At the molecular level, galangin co-administration was accompanied by suppression of NF-κB and NLRP3 inflammatory signaling, upregulation of the Nrf2/NQO1 antioxidant axis, and inhibition of p53 apoptotic signaling. In addition, mitochondrial biogenesis was enhanced, as indicated by upregulation of SIRT1/Tfam axis.</p> Conclusions <p>These findings provide the first evidence introducing galangin as a potential intervention against the polystyrene-evoked hepatotoxicity and unveiling the associating molecular changes. These changes involve the concurrent suppression of inflammation, oxidative stress, apoptosis, alongside the improvement of mitochondrial biogenesis.</p> Graphical abstract <p></p>