Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn’s disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn’s disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a−/−) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn’s disease when IL-17A or IL-17RA is inhibited. •IL-17 inhibition exacerbates Crohn’s disease and Abcb1a−/− mouse colitis•IL-17 inhibition weakens intestinal epithelial barrier function•IL-23 inhibition attenuates Crohn’s disease and Abcb1a−/− mouse colitis•IL-23 inhibition promotes a regulatory, anti-inflammatory environment in the gut IL-17 and IL-23 are potent inflammatory cytokines, yet their inhibition induced opposing effects in Crohn’s disease clinical trials. Using a mouse model of IBD, Maxwell et al. show that IL-17 inhibition weakens intestinal epithelial barrier function and increases inflammation whereas IL-23 inhibition enhances regulatory T cell accumulation, thereby dampening inflammation.