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Background: Drug-induced liver damage is a severe medical issue that affects people all over the world. Sorafenib has some side effects that cause liver injury. A dietary medicinal plant called Penthorum chinense Pursh. (PCP) has hepatoprotective properties. There are currently few reports on PCP's protective impact and mechanism against sorafenib-induced liver injury. Methods: To create a liver injury model, sorafenib was administered to BRL-3A cells. Cell viability assays, immunofluorescence tests, Western blotting, real-time quantitative PCR, and high-content imaging systems were utilized to examine PCP's effect and mechanism. Results: In this study, PCP treatment mitigated the liver damage caused by sorafenib by enhancing cell survival, lowering lipid reactive oxygen species and malondialdehyde levels, and elevating glutathione levels. In addition, PCP can enhance the protein expression of cystine/glutamate transporter xCT and glutathione peroxidase 4, reduce iron content and alleviate mitochondrial toxicity. Further mechanism studies revealed that PCP inhibited ferroptosis by promoting the production of nuclear factor E2-related factor 2 nuclear translocation and subsequently affecting target genes (HO-1 and NQO1). Conclusion: Together, PCP regulates the nuclear factor E2-related factor 2 pathway, which helps to lessen ferroptosis brought on by sorafenib. [ABSTRACT FROM AUTHOR]