Cerebral ischemia/reperfusion damage (CI/RI) is a recurring pathogenic process in post-ischemic stroke. Sanggenol L (SL) is a flavonoid of Morus alba root bark, which exhibits anticancer, neuroprotective, anti-inflammatory, and antioxidant properties. The signaling pathways involved underlying mechanisms of SL on CI/RI are not exploited. To examine the action of SL on CI/R-instigated brain injury through the inflammatory network of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) in rats was explored. Rats were separated into 5 sets: control, I/R-induced, I/R + Edaravone (ED, 6 mg/kg bw), I/R + SL (10 mg/kg), I/R + SL (20 mg/kg bw). CI/RI was induced by implanting a thread into the middle cerebral artery occlusion (MCAO) model. Cerebral damages were evaluated by using neurological deficit score, brain edema, brain infarct volume, histopathology, apoptosis, and oxidative stress in rats. SL inhibited cytokines, lipid peroxidation, and apoptosis while improving antioxidant status in MCAO rats. Furthermore, SL therapy reduced I/R-induced brain dysfunction and neuroinflammation by suppressing the HMGB1/TLR4/NF-κB pathways. SL could be a potential strong inhibitor of the CI/RI by suppression of the HMGB1/TLR4/NF-κB signaling pathway. SL's potential anti-inflammatory and antioxidant properties suggest it may be a promising therapeutic agent for CI/RI.