Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with a poor prognosis despite multiple available treatments. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has recently emerged as a promising strategy for cancer therapy, particularly in head and neck malignancies. However, its regulatory mechanisms remain largely unclear. In this study, we demonstrate that TP53 transcriptionally activates PHKG2, which promotes ferroptosis. PHKG2 enhances the activity of protein phosphatase 1 (PP1) by phosphorylating PPP1R3B, disrupting its interaction with PP1C. Activated PP1 dephosphorylates NRF2, promoting its nuclear export and suppressing GPX4 transcription, thereby enhancing ferroptosis sensitivity. Both in vitro and in vivo, PHKG2 overexpression significantly suppressed tumor growth and increased lipid peroxidation levels. These findings define a previously unrecognized TP53/PHKG2-PP1-NRF2 signaling axis in the regulation of ferroptosis in HNSCC and suggest a novel therapeutic target.