Objective To explore the therapeutic effect and mechanism of downregulating AQP-4 in cerebral ischemia-reperfusion injury model rats. Methods A total of 10 healthy male SD rats were used as the normal group and 30 rats were divided into model, downregulated AQP-4, and upregulated AQP-4 groups. AQP-4, BMP4, and P-Smad expression was examined by Western blot, TNF-α was detected by resonance light-scattering turbidimetry, and IL-1β levels were measured. Learning and memory abilities as well as neurological functions were evaluated in each group of rats. Water content was measured in brain tissue. Results Compared with the normal group, rats in the other three groups had a longer escape latency and lower number of crossings of the platform at each time point (P< 0.05). Compared with model and upregulated AQP-4 groups, the downregulated AQP-4 group had a shorter escape latency and higher number of platform crossings at each time point (P< 0.05). Compared with the normal group, neurological scores of model, upregulated AQP-4, and downregulated AQP-4 groups were increased, while water content in brain tissue was increased (P< 0. 05). Compared with model and upregulated AQP-4 groups, the downregulated AQP-4 group showed decreases in neurological scores and brain water content (P< 0. 05). Compared with the normal group, the other three groups of rats had increased TNF-α and IL-1β levels (P< 0. 05) Compared with model and upregulated AQP-4 groups, TNF-α and IL-1β levels were decreased in the downregulated AQP-4 group (P < 0.05). Compared with the normal group, the other three groups showed an increase in expression of AQP-4 and decreased expression of BMP4 and P-Smad (P< 0.05). Compared with model and upregulated AQP-4 groups, the downregulated AQP-4 group showed a decrease in expression of AQP-4 and increased expression of BMP4 and P-Smad (P< 0.05). Compared with the normal group, Na⁺ and P-dp were increased in the other three groups (P< 0.05). Compared with model and upregulated AQP-4 groups, the contents of Na⁺ and P-dp were decreased in the downregulated AQP-4 group (P< 0.05). Conclusions Downregulation of AQP-4 rescues the blood- brain barrier, improves learning and memory abilities, and reducea the inflammatory response in cerebral ischemia- reperfusion injury model rats through the BMP4 / Smad pathway.