Objective To investigate the effect of Lycium barbarum polysaccharide (LBP) on the polarization of BV2 microglia from M1 to M2 induced by lipopolysaccharide (LPS) and its mechanism. Methods The BV2 microglia were divided into control group, LPS group, and LBP treatment group (0.6, 0.9, 1.2) g/L. MTT assay was used to observe the cell viability of BV2 cells, and Griess assay was used to detect the release of NO. The levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were detected by ELISA. The expressions of Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and arginase-1 (Arg1) were detected by immunofluorescence cytochemistry. Western blot was used to evaluate the protein levels of ionized calcium-binding adaptor molecule-1 (Iba-1), TLR4, NF-κB, iNOS, and Arg1. Results There was no significant difference of the cell survival rate after treatment with different doses of LBP. Compared to those in the control group, in LPS group the BV2 microglia were activated with amoeba-like shape and increased release of NO, the expressions of Iba-1, TLR4, NF-κB, iNOS, TNF-α, IL-1β, and IL-6 were significantly increased, while the expressions of Arg1 and IL-10 was significantly decreased. In LBP group, Iba-1, TLR4, NF-κB, iNOS, TNF-α, IL-1β, and IL-6 were dramatically decreased and negatively correlated with the dose, while Arg1 and IL-10 were increased and positively correlated with the dose. Conclusion LBP inhibits activation of BV2 microglia induced by LPS and promots the M2 polarization, which may be realized through inhibiting TLR4/NF-κB signaling pathway.