Objective To explore the mechanism of Jisuishang Prescription for the treatment of rats with cervical spondylotic myelopathy (CSM) based on phosphatidylinositol 3⁃kinase (PI3K)/protein kinase B (AKT)/nuclear factor κB (NF⁃κB) p65 signaling pathway. Methods A total of 40 rats were randomly assigned to sham⁃operation group, modeling group, or low⁃, medium⁃, and high⁃dose Jisuishang Prescription groups, respectively, with 8 rats in each group. Except for the sham⁃operation group, rats in the remaining groups prepared for CSM model. After modeling, groups of Jisuishang Prescription in various doses received Jisuishang Prescription in corresponding concentrations (0.49 g/mL, 0.97 g/mL, 1.94 g/mL) for intragastric administration, whereas the sham⁃operation and modeling groups received intragastric administration of normal saline in equivalent volume, for a continuous 4⁃week intervention. On the second and fourth week of intragastric administration, Basso Beattie Bresnahan (BBB) spinal cord injury behavioral score, and forelimb grasping force were compared between rats in various groups. After 4 weeks of intragastric administration, cervical spinal tissues of rats in various groups were obtained. The HE staining was adopted to observe pathological changes of cervical spinal tissues in rats. The Nissl's staining was employed to observe Nissl bodies changes in cervical spinal tissues of rats. The expressions of interleukin (IL)⁃1β and IL⁃6 proteins in cervical spinal tissues of rats were detected by using the immunohistochemical method. The real⁃time fluorescent quantitative PCR and Western blot methods were used to detect mRNA and protein expressions of PI3K/AKT/NF⁃κB p65 signaling pathway associated molecules. Results Compared with the sham⁃operation group, the modeling group exhibited decreased BBB spinal cord injury behavioral score and forelimb grasping force, and rats in the modeling group presented as cavity structure changes in cervical spinal tissues, massive macrophages infiltration, decreased neurons and Nissl bodies, elevated expressions of IL⁃1β and IL⁃6 proteins, as well as elevated mRNA expressions of PI3K, AKT, NF⁃κB p65 genes, and elevated ratio of phosphorylated PI3K (p⁃PI3K)/PI3K, phosphorylated AKT (p⁃AKT)/AKT, phosphorylated NF⁃κB (p⁃NF⁃κB) p65/NF⁃κB p65 (P<0.05). Compared with the modeling group, the Jisuishang Prescription in various doses groups yielded elevated BBB spinal cord injury behavioral score and forelimb grasping force, and rats in the Jisuishang Prescription in various doses groups presented as reduced immune cell infiltration in cervical spinal tissues, reduced cavity structure, increased neurons and Nissl bodies, decreased expressions of IL⁃1β and IL⁃6 proteins, decreased mRNA expressions of PI3K, AKT, and NF⁃κB p65 genes, as well as decreased ratio of p⁃PI3K/PI3K, p⁃AKT/AKT, p⁃NF⁃κB p65/NF⁃κB p65, therein changes of the medium⁃dose Jisuishang Prescription was prominent (P<0.05). Conclusion Jisuishang Prescription may relieve inflammatory response in cervical spinal tissues, protect damaged neurons, ameliorate limb motor function of CSM rats model through inhibiting the activation of PI3K/AKT/NF⁃κB p65 signaling pathway.