Free Wanderer Powder (FWP) is a classic formula for depression with digestive dysfunctions, i.e., liver-depression and spleen-deficiency syndrome (LDSDS) in Chinese Medicine. But its protective mechanism has not been fully clarified. Here a chronic restraint stress (CRS) induced rat model showed depression with LDSDS in food intake, metabolism, and behaviour tests. Then 75 rats were randomly divided, and received CRS and different treatment with behaviour tests. Expressions of c-Fos and AMPA-type glutamate receptor subunits GluR1-3 in hippocampus CA1, CA3, DG and amygdala BLA were detected by immunohistochemistry, western blot and RT-PCR, respectively. In CRS rats, FWP alleviated depressive behaviour and c-Fos expression. FWP suppressed the increasement of GluR1 in CA1 and DG, p-GluR1 in CA1, and p-GluR2 and GluR3 in BLA. FWP also blocked the decrease of GluR1 and Glur2/3 in CA3, p-GluR1 in CA3, and p-GluR2 in CA1 and CA3. Furthermore, constituents of FWP and their potential targets were explored using UHPLC-MS and systematic bioinformatics analysis. There were 23 constituents identified in FWP, 9 of which regulated glutamatergic synapse. Together, these results suggest that FWP contains effective constituents and alleviates depression with LDSDS by regulating AMPA-type glutamate receptor homeostasis in amygdala and hippocampus.