The incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. Jiao-tai-wan (JTW), a well-known traditional Chinese medicine (TCM), has been approved to have hypoglycemic and antidepressant effects, respectively, but whether JTW has such dual effects and its potential mechanisms is still unknown. This study is to evaluate the dual therapeutic effects of JTW on chronic restraint stress (CRS)-induced DM combined with depression mice, and to explore the underlying mechanisms through network pharmacology.CRS was used on db/db mice for 21 days to induce depression-like behaviors, so as to obtain the DM combined with depression mouse model. Mice were treated with 0.9% saline (0.1 ml/10 g), JTW (3.2 mg/kg) and Fluoxetine (2.0 mg/kg), respectively. The effect of JTW was accessed by measuring fasting blood glucose (FBG) levels, conducting behavioral tests and observing histopathological change. The ELISA assay was used to evaluate the levels of inflammatory cytokines and the UHPLC-MS/MS method was used to determine the depression-related neurotransmitters levels in serum. The mechanism exploration of JTW against DM and depression were performed via a network pharmacological method.The results of blood glucose measurement showed that JTW has a therapeutic effect on db/db mice. Behavioral tests and the levels of depression-related neurotransmitters proved that JTW can effectively ameliorate depression-like symptoms in mice induced by CRS. In addition, JTW can also improve the inflammatory state and reduce the number of apoptotic cells in the hippocampus. According to network pharmacology, 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include INS, AKT1, IL-6, VEGF-A, TNF and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc. CONCLUSION: Our experimental study showed that JTW has hypoglycemic and antidepressant effects. The possible mechanism was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.© 2021. The Author(s).