Abstract: Objective To explore the protective effect and possible mechanism of Periplaneta americana powder on rats with spinal cord injury. Methods Forty-eight male SD rats were randomly divided into sham operation group, saline group, periplaneta americana powder group, and Toll-like receptors-4 inhibitor group. Except for the sham operation group, the rat spinal cord hemitransection injury model was constructed in the other three groups. The sham operation group received no treatment after operation, the saline group and the periplaneta americana powder group were given intragastric administration of equal volumes of normal saline and periplaneta americana powder (630 mg/kg), and the TLR4 inhibitor group was given intraperitoneal injection of TLR4 inhibitor (3 mg/kg ) deal with. On the 1 d, 3 d, 7 d, and 14 d after the operation, the motor function of the rat hind limbs was evaluated by BBB score, the histopathological changes of the spinal cord were observed by hematoxylin-eosin staining, and the changes in the number of neurons were observed by immunohistochemistry. The expressions of inflammatory factors IL-1, IL-6, IL-10 and TNF-α were detected by ELISA, and the expressions of TLR4, myeloid differentiation factor 88 (MyD88) and NF-κB p65 were detected by Western blot. Results Compared with the sham operation group, the BBB score and the number of neurons in the saline group were significantly decreased, while the degree of pathological damage, IL-1, IL-6, TNF-α, TLR4, MyD88, and NF-κB p65 levels were significantly increased (P < 0.05), compared with the saline group, the periplaneta americana powder group and the TLR4 inhibitor group increased the BBB score, the number of neurons, decreased the degree of pathological damage, IL-1, IL-6, TNF-α, TLR4, MyD88, NF-κB p65 levels (P < 0.05), compared with the TLR4 inhibitor group, the periplaneta americana powder group better increased the BBB score, the number of neurons, decreased the degree of pathological damage, and the expression of IL-1 and TNF-α. Conclusions Periplaneta americana powder can reduce the production of inflammatory factors after spinal cord injury by inhibiting the TLR4/MyD88/NF-κB pathway, and play a role in protecting nerves and promoting motor recovery.