Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) often associated with a Type 2 immune response. Although previous reports hint at a role for signal transducer and activator of transcription (STAT) 6 signaling in non-immune cells, the contribution of STAT6-activation particularly in intestinal epithelial cells (IECs) is still unknown. Dextran sodium sulfate (DSS)-induced colitis is a model for UC in mice that we applied here on animals with expression of a constitutively active version of STAT6 in IECs (VillinCre_STAT6vt mice). We report increased pathology and mortality due to enhanced and systemic inflammation in these mice. Bulk RNA sequencing of colonic tissue from naïve VillinCre_STAT6vt mice showed differential expression of more than 140 genes compared to control mice. Gene set enrichment analysis revealed STAT6-regulated expression of the unfolded protein response, MTORC- and MYC-signaling, and protein secretion pathways. A comparison of gene expression in the colon of naïve VillinCre_STAT6vt mice and a human single-cell RNA sequencing dataset of a patient cohort with IBD revealed overlapping changes in the epithelial and macrophage compartment compared to corresponding controls. In conclusion, we found that activation of STAT6 in the intestinal epithelium predisposes to exacerbated colitis and gut inflammation.