Background <p>Nasopharyngeal carcinoma (NPC) is a malignancy with high a mortality rate. This study investigates the impact of heme oxygenase-1 (HO-1) in cisplatin (CDDP) resistance in NPC.</p> Methods <p>The time-dependent effect of CDDP on two NPC cell lines (HK1 and C666-1) were investigated. CDDP-resistant cells were established by exposing the parental cells to increasing concentrations of CDDP. Parental cells received treatment of the HO-1 inducer Hemin while resistant cells received treatment of the HO-1 inhibitor ZnPP to explore the influence of HO-1 activity on CDDP resistance in NPC cell lines. Erastin was used to verify the effect of ferroptosis on CDDP sensitivity in cells. Parallel settings were performed in mouse xenograft tumor models for in vivo validation.</p> Results <p>CDDP time-dependently reduced growth and mobility of NPC cells within the initial 48&#xa0;h, but the cytotoxicity was no longer significantly enhanced afterward. HO-1 was upregulated in cells after CDDP treatment, showing correlation with acquired CDDP resistance. Inducing HO-1 activity in parental cells protected cells from oxidative damage, apoptosis, and ferroptosis, while suppressing HO-1 activity using ZnPP restored the therapeutic efficacy of CDDP in drug resistant cells. Moreover, the Erastin treatment also restored the cytotoxicity of CDDP to the resistant cells. In mice bearing xenograft tumors, treatment with either ZnPP or Erastin weakened the growth and weight of tumors.</p> Conclusion <p>This work suggests that HO-1 is pertinent to acquired CDDP resistance in NPC cells by suppressing oxidative stress and ferroptosis.</p>