ABSTRACT Introduction Brucellosis is an important zoonosis worldwide, affecting humans and animals. There are no specific medicines available to treat brucellosis. Astragalus polysaccharide (APS) is derived from Astragalus membranaceus and exhibits impressive bioactivity, including anti-aging, anti-tumor, and immunomodulatory functions. Methods Mice were intraperitoneally inoculated with Brucella melitensis M5 and then treated with APS intraperitoneally injection daily for 7 d. Results Compared to the M5-infected group, the lower bacteria loads in the APS-treated groups were proved, especially at the acute stage of infection. APS treatment relieved splenomegaly, excess expressions of several pro-inflammatory cytokines (including CXCL1, IFN-γ, IL-1β, IL-2, IL-12p70, and TNF-α). The raised level of IL-4 was observed in APS-treated mice. APS contributed to raising the ratio of M1 macrophage and reducing the ratio of M2 macrophage in the blood. Discussion The present study provides some evidence on the potential application of APS in controlling and treating brucellosis and should be further explored.