BACKGROUND TRPM2, a potentially important target for the treatment of ischemic stroke, is closely related to inflammation, oxidative stress and neuronal death caused by cerebral ischemia-reperfusion. The NLRP3 inflammasome is an important mediator of post-ischemic inflammation, its inhibition can also regulate the distribution of AQP4 to reduce brain edema. In addition, inhibiting TRPM2/NLRP3 improves neuronal injury and oxidative stress mediated by oxygen-glucose deprivation. Therefore, inhibiting the TRPM2/NLRP3 pathway may be a potential therapeutic approach for ischemic stroke. Wuling San (WLS) has anti-inflammatory and antioxidant properties and can be used clinically to treat hydrocephalus and cerebral edema. However, its specific effects on and mechanism of action in cerebral ischemia-reperfusion injury (CIRI) remain unclear. This study aimed to explore whether Wuling San (WLS) can improve CIRI and whether its potential mechanism is related to the regulation of TRPM2. METHODS The CIRI mouse model was constructed via bilateral carotid artery ligation and was intervened by gavage with different doses of WLS decoction. Behavioral, morphological, brain water content test and western blot (WB) analysis were used to determine the improvement effect of WLS on CIRI. The underlying mechanism of the protective effect of WLS was further explored. Therefore, a combined intervention of WLS and TRPM2 agonists was carried out in CIRI mice to determine whether the protective effect of WLS was reversed. RESULTS WLS administration was found to alleviate neurological deficits and cognitive impairment and reduce brain damage in CIRI model mice. Moreover, WLS reduced AQP4 expression and improved cerebral edema. CIRI disrupted the polarized distribution of AQP4, resulting in AQP4 being mainly distributed in astrocytes bodies, whereas the distribution around the endfeet of astrocytes and blood vessels decreased. Interestingly, WLS intervention promoted the normalization of AQP4 polarization. Notably, WLS inhibits the downregulation of TJs, which is beneficial for protecting the BBB and may further alleviate brain edema. In addition, WLS treatment inhibited microglial overactivation and mitigated CIRI by inhibiting inflammation, oxidative stress and apoptosis. Furthermore, WLS downregulated the expression of TRPM2 and NLRP3. By combining WLS with a TRPM2 agonist in CIRI mice, we found that TRPM2 overexpression reversed the downregulatory effect of WLS on the NLRP3 level. It simultaneously reversed the protective effect of WLS. CONCLUSIONS The present study is the first to prove that WLS improved CIRI and regulated the polarization distribution of AQP4 by targeting the TRPM2/NLRP3 pathway to alleviate brain edema, which is beneficial for neuroprotection and cognitive improvement after CIRI.