Aim To investigate the effect of butorphanol on neuronal pyroptosis in ischemic stroke rats and its role in protein kinase A (PKA)/cyclic adenosine phosphate (cAMP) response element binding protein (CREB). Methods A rat model of ischemic stroke was established using SD rats. All rats were divided into control group, model group, butorphanol low-dose group (butorphanol L group), butorphanol high-dose group (butorphanol H group) and butorphanol+PKA inhibitor (H-89) group. Neurological function was scored, TTC staining was used to detect cerebral infarction volume, and pathological characteristics of brain tissue were detected by HE staining. Neuronal pyroptosis was observed by uranium lead double staining in hippocampus. The expression of inflammassome NOD-like receptor thermal protein domain associated protein 3(NLRP3) and Caspase-1 were detected by immunofluorescence, and the contents of interleukin-1β (IL-1β), IL-18 and cAMP were detected by enzyme linked immunosorbent assay (ELISA). The expression levels of phosphorylated PKA (p-PKA), PKA, p-CREB and CREB protein were detected by Western blot. Results Compared with the control group, the brain space of rats in the model group was enlarged, the neuron cell membrane was defective, the nucleus and nuclear membrane were sunken and constricted, and the nerve function scores, cerebral infarction volume, NLRP3, Caspase-1, IL-1β and IL-18 levels were increased; the expression levels of cAMP, p-PKA/PKA and p-CREB/CREB protein were decreased (P＜0.05). Compared with the model group, the brain structure of butorphanol L and H groups was more complete, the neuronal cell structure was improved, the neural function scores, cerebral infarction volume, NLRP3, Caspase-1, IL-1β and IL-18 levels were decreased, and the protein expression levels of cAMP, p-PKA/PKA and p-CREB/CREB were increased (P＜0.05). Compared with butorphanol H group, butorphanol+H-89 group increased vacuolar degeneration of brain tissue, abnormal neuronal structure, neural function scores, cerebral infarction volume, NLRP3, Caspase-1, IL-1β and IL-18 levels; and the expression levels of cAMP, p-PKA/PKA and p-CREB/CREB protein were decreased (P＜0.05). Conclusion Butorphanol significantly inhibits neuronal pyroptosis in ischemic stroke rats, which may be related to the activation of PKA/CREB signaling pathway.