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Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes play a vital role in tissue repair and immunomodulation, mitigating inflammatory bowel disease. However, its effect on dextran sodium sulfate (DSS)-induced chronic experimental colitis mice is poorly understood.Methods In our study, the DSS-induced chronic colitis mice model was established, and the exosomes were used by intraperitoneal injection into mice. The mice disease activity index (DAI), body weight, colon length, tissue H&E, immunohistochemistry, cytokines expression were analyzed, and the proportion of T cells was evaluated by multicolour flow cytometry. RNA sequencing was performed to detect the signaling pathway.Results HucMSC exosomes administration diminished colon shortening, body-weight loss, bleeding, and colon injury. The levels of IFN-γ and IL-17A were decreased, while the levels of IL-4, IL-10 and TGF-β were increased in the serum and colon tissue of mice treated with exosomes. Percentages of CD4 +CD25+Foxp3+ Treg cells and CD4+IL4+ Th2 cells were grown in the spleen of mice treated with exosomes. Exosomes attenuate colonic inflammation via the FoxO1 signaling pathway. Downregulation of FoxO1 reduced the therapeutic effects of hucMSCs exosomes in vitro and in vivo.Conclusions Our study suggested that the hucMSC exosomes could alleviate the intestinal inflammatory response of DSS-induced chronic experimental colitis in mice by activating the FoxO1 signaling pathway, which provides a potential therapeutic mechanism for hucMSC exosomes in treating IBD.