Aim: This study aimed to investigate whether celastrol (CEL) could alleviate incision-induced pain and decipher its possible mechanism. Materials and methods: Sprague-Dawley rats were randomly divided into five groups: naive, vehicle, CEL (5 mu g/paw, 10 mu g/paw and 20 mu g/paw). CEL or vehicle was administered intraplantarly before plantar surgical incision. Histological examinations of skin tissues were performed after HE staining. Additionally, immunohistochemical staining, RT-PCR and western blot were performed to analyse macrophages, proinflammatory cytokines, SARM and NF-kappa B expression, respectively. Moreover, the previous mentioned factors were re-evaluated after suppressing SARM expression by shRNA. Key findings: The plantar incision rats displayed pain-related behaviours and inflammatory infiltration in the skin. The mRNA levels of proinflammatory cytokines, such as IL-1 beta, IL-6, and TNF alpha were significantly upregulated in the skin of surgical rats. The expression of sterile alpha- and armadillo-motif-containing protein (SARM) was downregulated and nuclear factor kappa-B (NF-kappa B) was activated. Interestingly, CEL could partially restore the pain-related behavioural changes. Furthermore, molecular mechanism of CEL was explored, that included significantly reduction of proinflammatory cytokines mRNA expressions, a significant decrease of p-p65 and p65 levels and a markedly increase of SARM and IkB alpha expressions in skin tissues. However, supression SARM by shRNA partially eliminated those protective effect of CEL. Significance: Our data suggest that intraplantarly administration of CEL attenuates inflammatory and acute pain. This finding could be attributed to regulation of the NF-kappa B signalling pathway via SARM. These results provide pre-clinical evidence supporting the use of CEL in the treatment of surgical pain.