Glioblastoma (GBM) is a highly aggressive brain tumor with limited effective treatment options. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a potential vulnerability in GBM, yet its regulatory mechanisms remain poorly defined. In this study, we investigated the impact of TP53 mutations on ferroptosis sensitivity and identified TP63 as a critical modulator in this process. Integrative transcriptomic and mutational analyses of GBM samples from The Cancer Genome Atlas (TCGA) revealed that TP53 mutations are associated with poor prognosis and altered expression of genes involved in iron homeostasis and glutathione metabolism. Notably, TP63 (mainly ΔNp63 isoform) expression was markedly upregulated in TP53-mutant GBM. Functional experiments demonstrated that TP63 suppresses ferroptosis by reducing reactive oxygen species (ROS) accumulation and lipid peroxidation. Mechanistic studies further showed that TP53 mutations activate the Wnt/β-catenin signaling pathway, leading to nuclear accumulation of β-catenin, which transcriptionally upregulates TP63. In turn, TP63 directly enhances GPX4 expression, a key inhibitor of ferroptosis. These findings define a novel TP53 mutation-Wnt/β-catenin-TP63-GPX4 signaling axis that promotes ferroptosis resistance in GBM and deepen our understanding of ferroptosis regulation in this malignancy.