This study investigates the role of NSUN2, a key RNA m5C methyltransferase, in non-small cell lung cancer (NSCLC). High expression of NSUN2 is associated with poor outcomes in NSCLC patients. RNA-seq analysis revealed that the antioxidant-promoting transcription factor NRF2 is a target of NSUN2. Depleting NSUN2 decreases NRF2 expression and increases NSCLC cell sensitivity to ferroptosis activators both in vitro and in vivo. The methylated-RIP-qPCR assay showed that NRF2 mRNA has higher m5C levels when NSUN2 is overexpressed, but not in NSUN2 methyltransferase-deficient cells. Mechanistically, NSUN2 upregulates NRF2 expression by enhancing the stability of NRF2 mRNA through m5C modification within its 5'UTR region, recognized by the m5C reader protein YBX1. Knocking down NRF2 diminishes the proliferation, migration, and ferroptosis tolerance mediated by NSUN2 overexpression. These findings suggest that NSUN2 sustains NRF2 expression through an m5C–YBX1 axis, providing a novel therapeutic target for NSCLC.This study investigates the role of NSUN2, a key RNA m5C methyltransferase, in non-small cell lung cancer (NSCLC). High expression of NSUN2 is associated with poor outcomes in NSCLC patients. RNA-seq analysis revealed that the antioxidant-promoting transcription factor NRF2 is a target of NSUN2. Depleting NSUN2 decreases NRF2 expression and increases NSCLC cell sensitivity to ferroptosis activators both in vitro and in vivo. The methylated-RIP-qPCR assay showed that NRF2 mRNA has higher m5C levels when NSUN2 is overexpressed, but not in NSUN2 methyltransferase-deficient cells. Mechanistically, NSUN2 upregulates NRF2 expression by enhancing the stability of NRF2 mRNA through m5C modification within its 5'UTR region, recognized by the m5C reader protein YBX1. Knocking down NRF2 diminishes the proliferation, migration, and ferroptosis tolerance mediated by NSUN2 overexpression. These findings suggest that NSUN2 sustains NRF2 expression through an m5C–YBX1 axis, providing a novel therapeutic target for NSCLC.