AbstractThe nuclearN6‐methyladenosine (m6A) reader YT521‐B homology‐domain‐containing protein 1 (YTHDC1) is required to maintain embryonic stem cell identity. However, little is known about its biological functions in intestinal‐resident macrophages and inflammatory bowel disease (IBD). Herein, it is demonstrated that macrophage‐specific depletion or insufficiency of YTHDC1 accelerates IBD development in animal models. On the molecular basis, YTHDC1 reduction in IBD‐derived macrophages is attributed to Zinc finger protein 36 (ZFP36)‐induced mRNA degradation. Importantly, transcriptome profiling and mechanistic assays unveil that YTHDC1 in macrophages regulates Ras homolog family member H (RHOH) to suppress inflammatory responses and fine‐tunes NME nucleoside diphosphate kinase 1 (NME1) to enhance the integrity of colonic epithelial barrier, respectively. Collectively, this study identifies YTHDC1 as an important factor for the resolution of inflammatory responses and restoration of colonic epithelial barrier in the setting of IBD.