Objective To investigate the effect of mild hypothermia on neurological function in rats with spinal cord injury (SCI) based on the adenosine monophosphate activated protein kinase (AMPK)/Nod-like receptor protein 3 (NLRP3) pathway. MethodsFifty 7-8 weeks old SPF male Sprague Dawley rats were used to establish rat model of SCI by Allen’s method. Among them, 48 successfully modeled rats were randomly divided into SCI group, mild hypothermia group (SCI+mild hypothermia treatment), and Compound C group (SCI+mild hypothermia+20 mg/kg AMPK/NLRP3 pathway inhibitor Compound C), with 16 rats in each group; another 16 normal rats with laminectomy were selected as sham-operation group. Basso-Beattie-Bresnahan (BBB) score was used to evaluate the motor ability of rats at 1, 3, 7, 14 days after treatment. After 14 days, the rats were sacrificed, and the spinal cord histopathological morphology was observed by HE staining, the neuronal apoptosis in spinal cord tissue was detected by TUNEL assay, and the serum levels of interleukin 2 (IL-2), IL-6, transforming growth factor β1 (TGF-β1), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by ELISA. The expression of AMPK/NLRP3 pathway protein, including B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved-Caspase-9 were detected by Western blot. Results At 1 day after treatment, the rats in SCI group, mild hypothermia group, and Compound C group did not recover their motor ability; at 3, 7, and 14 days, the BBB score of SCI group was significantly lower than that of SCI group (P<0.05), the BBB score of mild hypothermia group was significantly higher than that of SCI group (P<0.05), and the BBB score of Compound C group was significantly lower than that of mild hypothermia group (P<0.05). Compared with the sham-operation group, the SCI group displayed obvious pathological changes in the spinal cord tissue, with disordered tissue architecture, inflammatory infiltration, and blurred interstitial boundaries. The neuronal apoptosis rate, Bax/Bcl-2 ratio, cleaved Caspase-9 expression, NLRP3 protein expression, serum IL-2, IL-6, and MDA levels were elevated, whereas serum TGF-β1, SOD levels, and spinal cord phosphorylation AMPK/AMPK protein expression significantly decreased (P<0.05). Compared with the SCI group, the above phenomena significantly improved in the mild hypothermia group (P<0.05), while the Compound C group showed the opposite trend of change compared to the mild hypothermia group (P<0.05). Conclusion Mild hypothermia can attenuate neurological dysfunction after SCI in rats, potentially by activating the AMPK/NLRP3 pathway.