Objective To investigate the effect of CCL2 neutralizing antibody on pain behavior in skin/muscle incision and retraction (SMIR) model rats, and study the possible mechanism of action. Methods SD rats were divided into sham, SMIR model, SMIR+IgG and SMIR+CCL2 neutralizing antibody groups, with 8 rats in each group. The nociceptive sensitivity was assessed by behavioral tests; the levels of M1 and M2 type macrophage marker genes were confirmed by qRT-PCR or immunofluorescence in the dorsal root ganglion (DRG), and macrophage metabolic capacity was assessed by glycolytic assays. Results The 50% mechanical withdrawal threshold (MWT) of the affected foot was lower (P<0.05), and the duration of foot reduction (CPWL) was prolonged (P<0.05) in the rats in the SMIR model group postoperatively, whereas the application of CCL2-neutralizing antibody improved these behavioral abnormalities (P<0.05). There was no significant difference in heat-shrinking foot latency (PWL) between the groups (P>0.05). Besides, the levels of inflammation-related genes CD80, iNOS and IL-12 were increased (P<0.05), while the levels of anti-inflammatory genes CD206, Arg1 and IL-10 were decreased (P<0.05) in the rats of the SMIR model group. The aberrant changes in the expression of these genes were attenuated after the intervention of the CCL2-neutralizing antibody (P<0.05). Moreover, relative to the sham-operated group, the glycolytic metabolic activity of macrophages in the SMIR model group was enhanced, and their extracellular acidification rate (ECAR), ATP production, glucose uptake, and lactate production were elevated (P<0.05). These metabolic indexes were reduced after the intervention of the CCL2 neutralizing antibody (P<0.05). Conclusion CCL2 neutralizing antibody effectively alleviates mechanical nociceptive hypersensitivity in SMIR model rats while reducing macrophage glycolytic metabolic activity and regulating the expression of inflammation-related genes