Abstract: The incidence of depression is increasing annually, with its etiology still unclear. The gut microbiota plays a significant role in the onset and development of depression, participating through pathways such as inflammatory responses, hypothalamic-pituitary-adrenal axis axis regulation, monoamine neurotransmitter modulation, and neurotrophic factor regulation. Thus, modulating the gut microbiota has become an emerging direction for treating depression. Xiaoyao San, a classical traditional Chinese medicine formula, has shown remarkable effectiveness in treating depression, with significant advantages. Numerous studies have confirmed that Xiaoyao San exerts its antidepressant effects by regulating the gut microbiota. This review summarizes recent studies on the changes in gut microbiota in patients with depression treated with Xiaoyao San, the role of gut microbiota in the pathogenesis of depression, and the antidepressant mechanisms of Xiaoyao San through gut microbiota regulation. By summarizing these studies, this review provides references for the prevention and treatment of depression and the further development of traditional Chinese medicine.