Objective. To comparatively examine the effectiveness and safety of the combination therapy of traditional Chinese medicine formula Bushen-Shugan granule and psychotherapy (BSSG-P) and Chinese herbal medicine Bushen-Shugan granule (BSSG) alone in the treatment of moderate to serious mood disorder in menopausal women. Methods. In our previous clinical studies, BSSG-P had been proved to be superior to BSSG, psychological treatment, and placebo in improving mild mood disorder in menopausal women. In this study, we analyzed the efficacy of BSSG-P and BSSG in the treatment of moderate to serious mood disorder. Eighty-five eligible participants, who were diagnosed as menopausal women with moderate to serious mood disorder and categorized as kidney deficiency and liver-qi stagnation pattern, were randomly assigned into two groups and treated with BSSG-P or BSSG. They were subjected to an 8-week treatment period and a 4-week follow-up study. The primary outcome instrument was the Greene Climacteric Scale, Self-Rating Depression Scale (SDS), and Self-Rating Anxiety Scale (SAS), respectively. Results. When comparing all time points with baseline, both BSSG-P and BSSG markedly decreased the total score of Greene, SDS, and SAS and the score of each dimension, in which BSSG-P exerted superior effect after 8-week treatment and 4-week follow-up (P<0.05). Furthermore, BSSG-P also showed great advantage in reducing the score of Greene, SDS, and SAS for menopausal women with moderate mood disorder at the end of the 8th and 12th week when compared with BSSG (P < 0.05), whereas there was no significant difference between groups at any time point for patients with serious mood disorder (P>0.05). No serious event occurred in both groups, and no significant difference was found between groups in adverse event proportion. Conclusions. BSSG-P was superior to BSSG in improving the physical and psychological symptoms of menopausal women with mood disorder. For patients with moderate mood disorder, BSSG-P showed obvious advantages; however, no superiority was observed for serious mood disorder.