Inflammatory bowel diseases (IBD) are prevalent and debilitating diseases; their clinical remedy is desperately unmet. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple immunomodulatory effects, which are attributed to their efficacy in the IBD rodent model. Optimization of MSC regimes in IBD is a crucial step for their further clinical application. Wogonin is a flavonoid‐like compound, which showed extensive immunomodulatory and adjuvant effects. This research is aimed at investigating whether and how Wogonin boosted the therapeutic efficiency of MSCs on DSS‐induced colitis. Our results showed that the MSC treatment with Wogonin significantly alleviated the intestinal inflammation in IBD mice by increased IL‐10 expression. In vitro experiments, Wogonin obviously raised the IL‐10 production and ROS levels of MSCs in a dose‐dependent manner. Meanwhile, western blot data suggested Wogonin improves the IL‐10 production by inducing transcript factor HIF‐1α expression via AKT/GSK3β signal pathway. Finally, the favorable effects of Wogonin on MSCs were confirmed by IL‐10 blockade experiment in vivo. Together, our results suggested that Wogonin significantly increased the IL‐10 production and enhanced the therapeutic effects of MSCs in DSS‐induced colitis. This work suggested Wogonin as a novel optimal strategy for MSC clinical application.