The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that ΔNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with ΔNp63α and mediated its degradation. Here, we report that ΔNp63 associates with the B56α regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3β (GSK3β), leading to a dramatic inhibition of PP2A-mediated GSK3β reactivation. The inhibitory effect of ΔNp63 on GSK3β mediates a decrease in phosphorylation levels of β-catenin, which induces intranuclear accumulation of β-catenin and activates β-catenin-dependent transcription. Our results suggest that ΔNp63 isotypes act as positive regulators of the β-catenin signaling pathway, providing a basis for their oncogenic properties.