Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (T(FH)) cells in the gut. The expression of ATF3 in CD4(+) T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4(+) T cells (CD4(cre)Atf3(fl/fl) ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of T(FH) cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4(cre)Atf3(fl/fl) mice compared with Atf3(fl/fl) littermate controls. The defective T(FH) cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of T(FH) or IgA(+) B cells caused significant remission of colitis in CD4(cre)Atf3(fl/fl) mice, indicating the T(FH)-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4(+) T cells. In summary, we demonstrated ATF3 as a regulator of T(FH) cells in the gut, which may represent a potential immunotherapeutic target in colitis.