Chaihu-Shugan-San (CSS) is a classical prescription used to treat depression. According to the traditional Chinese medicine (TCM) principle, the 2 decomposed recipes in CSS exert synergistic effects, including Shu Gan (stagnated Gan-Qi dispersion) and Rou Gan (pain alleviation). However, the specific mechanism and compatibility rule remain to be explored. We aimed to analyze the advantage of TCM compatibility in CSS prescriptions and explore its anti-depression mechanisms.