Axin and p53 are tumor suppressors, controlling cell growth, apoptosis, and development. We show that Axin interacts with homeodomain‐interacting protein kinase‐2 (HIPK2), which is linked to UV‐induced p53‐dependent apoptosis by interacting with, and phosphorylating Ser 46 of, p53. In addition to association with p53 via HIPK2, Axin contains a separate domain that directly interacts with p53 at their physiological concentrations. Axin stimulates p53‐dependent reporter transcription in 293 cells, but not in 293T, H1299, or SaOS‐2 cells that are defective in p53 signaling. Axin, but not AxinΔHIPK2, activates HIPK2‐mediated p53 phosphorylation at Ser 46, facilitating p53‐dependent transcriptional activity and apoptosis. Specific knockdown of Axin by siRNA reduced UV‐induced Ser‐46 phosphorylation and apoptosis. Kinase‐dead HIPK2 reduced Axin‐induced p53‐dependent transcriptional activity, indicating that Axin stimulates p53 function through HIPK2 kinase activity. Interestingly, HIPK2ΔAxin that lacks its Axin‐binding region acts as a dominant‐positive form in p53 activation, suggesting that the Axin‐binding region of HIPK2 is a putative autoinhibitory domain. These results show that Axin acts as a tumor suppressor by facilitating p53 function through integration of multiple factors.