Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we showed that metallothionein (MT)-1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The mRNA and protein expression of MT-1G is remarkably induced by sorafenib, but not other clinically-relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), but not p53 and hypoxia-inducible factor 1-alpha (HIF1α), is essential for induction of MT-1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT-1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT-1G in sorafenib resistance involves the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT-1G by RNAi increases glutathione depletion and lipid peroxidation, which contributes to sorafenib-induced ferroptosis.