The molecular mechanisms contributing to the regulation of Th17-mediated inflammation remain underexplored. We here report a SUMO-specific protease (SENP)2-mediated pathway induced in pathogenic Th17 cells that restricts the pathogenesis of inflammatory colitis. SENP2 regulates the maturation of small ubiquitin-like modifiers (SUMO) and recycles SUMO from the substrate proteins. We find higher levels of SENP2 in pathogenic Th17 cells. By deletingSenp2in T-cell lineages in mice, we demonstrate that the lack ofSenp2exacerbates the severity of experimental colitis, which is linked to elevated levels of GM-CSF+IL-17A+pathogenic Th17 cells and more severe dysbiosis of the intestinal microbiome. Adoptive transfer experiments demonstrate the cell-autonomous effect ofSenp2in restraining Th17 differentiation and colitis. The enzymatic activity of SENP2 is important for deSUMOylation of Smad4, which reduces Smad4 nuclear entry andRorcexpression. Our findings reveal a SENP2-mediated regulatory axis in the pathogenicity of Th17 cells.