STAT2 is a pivotal component in type I IFNs signaling pathway that activates the transcription of antiproliferative, apoptotic and antiviral genes. Work from our lab and others have demonstrated that lack of STAT2 impairs the antitumor effects of type I IFNs thus supporting that type I IFNs suppress tumor growth via STAT2. With the availability of Stat2-/- mice, we first interrogated the tumor suppressive role of STAT2 by employing the AOM/DSS model of colitis-associated cancer and the spontaneous Apc+/min sporadic model of colorectal cancer. In both models, lack of STAT2, unexpectedly, did not increase but instead reduced the number of adenomas when compared to wild type mice. Our new findings show that STAT2 may also enable progression of colorectal cancer. Conversion of adenomas to adenocarcinomas is linked to loss of p53 function which occurs in > 50% of colorectal cancers, therefore, we determined the consequence of STAT2 knockdown in isogenic p53 null and p53-wild type colon tumor cells. STAT2 depletion reduced migration and invasion of p53 null colon carcinoma tumor cells while no effect was observed in cells carrying wild type p53. STAT2 knockdown in p53 null tumor cells also increased E-cadherin protein levels, a marker of epithelial-mesenchymal transition. Conversely, overexpression of STAT2 in p53 null cells reduced E-cadherin protein. In vivo, STAT2 knockdown delayed tumor growth of p53 null cells. Furthermore, using a liver-metastasis tumor model, STAT2 knockdown prevented the formation of tumor nodules in the liver. RNA-seq profiling of subcutaneous p53 null tumors revealed several genes were downregulated by STAT2 knockdown. Clinically, analysis of the TCGA database showed a STAT2 transcriptional signature in colorectal tumors that we are presently correlating with p53 alterations. Overall, we conclude that STAT2 is tumorigenic and can contribute to disease progression by promoting migration and invasion when normal p53 function is lost.