ZAKα-driven ribotoxic stress response (RSR) has been shown to trigger diverse biological effects. Nevertheless, its role in the pathogenesis of ulcerative colitis (UC) remained unclear. This study aimed to determine the role of ZAKα in the development of UC. Our study found that ZAKα expression was significantly increased in colonic epithelium of UC patients and DSS-colitis mouse models. Moreover, the expression level of ZAKα mRNA showed a positive correlation with disease activity. In the colitis model, Vemurafenib, the ZAKα inhibitor, treatment reduced colonic inflammation and ameliorated intestinal mucosal barrier damage, while Anisomycin, the RSR agonist, showed the opposite effect. In vitro experiments demonstrated that Anisomycin induced pyroptosis instead of apoptosis in C26 cell line. Western blot analysis revealed that Anisomycin triggered pyroptosis via the Caspase-11/GSDMD pathway. Further animal studies confirmed that Vemurafenib downregulated this pathway, reducing colonic epithelial cell pyroptosis. Finally, blocking Caspase-11 reduced severity of DSS-induced colitis in Anisomycin-treated mice. In all, ZAKα seems to play a crucial role in the pathogenesis of colitis, as it promotes pyroptosis in colonic epithelial cells and exacerbates colitis in part by upregulating the Caspase-11/GSDMD axis.