To study the mechanism of Xiaoyaosan Decoction in regulating appetite by soothing liver to relieve depression, and invigorating spleen. Methods:SD male rats were randomly divided into four groups; the control group (A), the 7-day model group (B), the 21-day model group (C) and the Xiaoyaosan (XYS) group (D). Except for the control group, models of the other three groups were established by chronic restraint stress method 3 h a day persistently for 7 days, 21 days and 21 days respectively, while Xiaoyaosan Decoction was given in the XYS group at the same time. Body weight, food intake, animal behavior, and the level of D-xylose in the serum were detected in all four groups; the mRNA and protein levels of leptin receptor(ob-R) and-melanocyte stimulating hormone(-MSH) were measured by RT-qPCR and immunofluorescence double staining method. Results:Compared with the control group, the body weight, food intake and the level of D-xylose in the serum were significantly decreased in group C, with decreased autonomous activity and new environment exploratory behavior; while the result of group D showed that Xiaoyaosan Decoction could regulate all of those mentioned above. All together indicated that chronic restraint animal model with liver depression and spleen deficiency can be established by restraining 3 h a day, for 21 days continually; the expression of ob-R and-MSH increased in arcuate nucleus (ARC) of chronic restraint stress rats and Xiaoyaosan Decoction could reduce the expression. Conclusion:The expression of ob-R and-MSH can be regulated by Xiaoyaosan Decoction, indicating that ob-R and-MSH may be the targets of Xiaoyaosan Decoction in regulating the function of spleen and stomach through soothing the liver and invigorating the spleen so as to regulate appetite and energy metabolism.