Objective: The aim of the study was to assess the effectiveness of Chinese herbal medicine combined with traditional Chinese medicine (TCM)-based psychotherapy (TBP) on perimenopausal depression (PMD). Methods: This multicenter, randomized, placebo-controlled clinical trial was conducted in nine hospitals in China between August 2015 and June 2017. The study included 307 women with PMD who were divided randomly into two treatment groups: the Bushen Tiaogan formula (BSTG) plus TBP (n = 156) and placebo plus TBP (n = 151). All participants underwent treatment for 8 weeks and were followed up for 4 weeks. The primary outcome measures included scores of the Greene Climacteric Scale (GCS), Self-Rating Depression Scale (SDS), and Self-Rating Anxiety Scale (SAS). Secondary outcomes included serum levels of sex hormones and lipids, as well as adverse events. Results: The average GCS, SDS, and SAS scores after treatment were significantly lower in the BSTG-plus-TBP group than those in the placebo-plus-TBP group, and the differences were greatest at the end of the 12th week: the average GCS scores were 10.8 in the BSTG-plus-TBP group versus 18.5 in the placebo-plus-TBP group (P < 0.001); the average SDS scores were 30.7 in the BSTG-plus-TBP group versus 45.4 in the placebo-plus-TBP group (P < 0.001); the SAS scores were 28.6 in the BSTG-plus-TBP group versus 42.6 in the placebo-plus-TBP group (P < 0.001). In addition, treatments with BSTG plus TBP significantly reduced the levels of basal follicle-stimulating hormone (P = 0.045) and triglycerides (P = 0.039) and increased the level of high-density lipoprotein cholesterol (P < 0.001) compared to placebo treatments with TBP. No serious adverse events occurred, and the safety indices of complete blood counts, renal function, and liver function were within normal ranges, before and after treatments. Conclusions: Treatment with BSTG formula plus TBP was more effective than TBP alone for improving PMD symptoms, sexual hormone levels, and blood lipid conditions in women with mild PMD.