Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4+ T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4+ T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.