Nasopharyngeal carcinoma (NPC) is one of the common malignant tumors in clinic. In the current study, we aim to investigate the effects of PRMT4 on erastin-induced ferroptosis in NPC by cisplatin resistant. PRMT4 expression in patients with NPC by cisplatin was upregulated. PRMT4 upregulation promoted cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. PRMT4 downregulation reduced cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. PRMT4 promoted tumor volume in mice model of erastin-induced NPC by cisplatin. PRMT4 upregulation reduced erastin-induced ferroptosis in NPC cisplatin-resistant cells by mitochondrial damage. PRMT4 upregulation induced Nrf2 protein expression in model of erastin-induced NPC by cisplatin. Nrf2 reduced the effects of si-PRMT4 on cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. Nrf2 inhibitor reduced the effects of PRMT4 on cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. Nrf2 reduced the effects of si-PRMT4 on erastin-induced ferroptosis in NPC cisplatin-resistant cells by mitochondrial damage. PRMT4 protein interlinked with Nrf2 protein to decrease Nrf2 ubiquitination. Methylation increased PRMT4 DNA stability. Collectively, our data reveal that PRMT4 reduced erastin-induced ferroptosis in NPC cisplatin-resistant cells by Nrf2/GPX4 pathway, suggesting that targeting PRMT4 may present as a potential strategy against the development of NPC.