It has been reported that Banxia-houpo decoction (BXHPD) serves as the anti-depressant treatment for a mild and severe depressive disease with limited side effects. The present study was performed to evaluate the protective effect of BXHPD on chronic unpredicted mild stress (CUMS)-induced depression and explore its effect on TrkA/Akt-mediated microglia polarization. The CUMS procedure was carried out, and the mice were intragastrically treated with BXHPD once daily. The selective TrkA inhibitor GW441756 was applied to further investigate the role of TrkA in BXHPD-mediated microglia polarization. The behaviour test including open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), tail suspension test (TST) and forced swim test (FST) was performed. The concentrations of pro-inflammatory cytokines IL-6, TNF-α, IL-1β, IL-12 and anti-inflammatory cytokines IL-4, IL-10 were determined using Enzyme-linked immunosorbent assay. The population of Iba1+ cells and the length of microglia processes were observed under the fluorescence microscope. The mRNA expressions of Arg1, Ym1 and Fizzl1 were measured by PCR. The protein expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3 were detected by western blot. Our results showed that BXHPD attenuated CUMS-induced depressive-like behaviour, promoted anti-inflammatory cytokines, inhibited pro-inflammatory cytokines, suppressed microglia activation, promoted M2 phenotype-specific indices and upregulated the expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3. The above beneficial effect of BXHPD can be blocked by TrkA inhibitor GW441756. This work demonstrated that BXHPD exerted an anti-depressant effect by promoting M2 phenotype microglia polarization via TrkA/Akt pathway.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.