As a member of the 11-gene "death-from-cancer" gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after deletion in mice. We aimed to investigate the function of USP22 in intestinal inflammation as well as inflammation-associated CRC. We evaluated the effects of a conditional, intestine-specific knockout of during dextran sodium sulfate (DSS)-induced colitis and in a model for inflammation-associated CRC. Mice were analyzed phenotypically and histologically. Differentially regulated genes were identified in USP22-deficient human CRC cells and the occupancy of active histone markers was determined using chromatin immunoprecipitation. The knockout of increased inflammation-associated symptoms after DSS treatment locally and systemically. In addition, deletion resulted in increased inflammation-associated colorectal tumor growth. Mechanistically, USP22 depletion in human CRC cells induced a profound upregulation of secreted protein acidic and rich in cysteine () by affecting H3K27ac and H2Bub1 occupancy on the gene. The induction of was confirmed in vivo in our intestinal -deficient mice. Together, our findings uncover that USP22 controls expression and inflammation intensity in colitis and CRC.