HIPK1 (homeodomain interacting protein kinase 1) is a serine/threonine kinase that belongs to the CMGC superfamily. Emerging data point to the role of HIPK1 in cancer, but it is still not clear whether it acts as a tumor suppressor or promoter. Here we identified HIPK1 as a kinase that is significantly overexpressed in colorectal cancer (CRC) and whose expression is stage-dependent. Being abundantly expressed at the onset of the disease, the HIPK1 level gradually decreased as tumor stage progressed. To further uncover how this factor regulates tumorigenesis and establish whether it constitutes an early factor necessary for neoplastic transformation or for cellular defense, we studied the effect of its overexpression in vitro by investigating various cancer-related signaling cascades. We found that HIPK1 mostly regulates the p53 signaling pathway both in HCT116 and HeLa cells. By phosphorylating p53 on its serine-15, HIPK1 favored its transactivation potential, which led to a rise in p21 protein level and a decline in cell proliferation. Assuming that HIPK1 could impede CRC growth by turning on the p53/p21 pathway, we then checked p21 mRNA levels in patients. Interestingly, p21 transcripts were only increased in a subset of patients expressing high levels of HIPK1. Unlike the rest of the cohort, the majority of these patients hosted a native p53 protein, meaning that such a pro-survival pathway (HIPK1+ > p53 > p21) is active in patients, and that HIPK1 acts rather as a tumor suppressor.