[Abstract] Objective To investigate the effect of CCL2-neutralizing antibody on the pain behavior of skin/muscle incision and retraction (SMIR) rats and its main regulatory mechanism. Methods Male SD rats were randomly divided into sham group, SMIR group, SMIR + IgG, SMIR + CCL2-neutralizing antibody group, there were 8 rats in each group. We first observed the pain behavior of the affected foot and the contralateral foot. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in serum were detected by ELISA. The expressions of CCL2/CCR2/NR2B and PI3K/AKT pathway-related proteins were confirmed by Western blot in DRGS. Results Compared with the sham group, the rats in the SMIR group showed a significant pain behavior change after SMIR, which was manifested as a sustained reduction in MWT. CCL2-neutralizing antibody could increase MWT and decrease the number of leg raising/licking of the affected foot in SMIR model rats. Besides, the CCL2-neutralizing antibody can reduce the levels of IL-1β, IL-6, and TNF-α in the serum of the SMIR model. CCL2-neutralizing antibody can also downregulate CCL2, CCR2, and NR2B proteins, and inhibit PI3K, and AKT phosphorylation in DRG of the SMIR model rats. Conclusion CCL2-neutralizing antibody can reduce persistent postoperative pain and inflammation, and the mechanism may be related to the downregulation of the CCL2/CCR2/NR2B and PI3K/AKT pathways.