〔Abstract〕 Objective To explore the mechanism by which total flavones of rhododendron(TFR) protect against cerebral ischemia-reperfusion(I/R) injury by inhibiting the TNF-α/caspase-8/caspase-3 signaling pathway. Methods The middle cerebral artery occlusion(MCAO) method was used to establish the rat I/R model. Rats were randomly divided into Sham surgery, MCAO, and post-I/R intervention with TFR 200 mg/kg(TFR 200 mg/kg) groups. After establishing the MCAO rat model, rats in the TFR 200 mg/kg group were administered TFR(200 mg/kg) solution for 14 consecutive days following I/R injury surgery. Hematoxylin-Eosin(HE) staining was used to observe neurological function scoring, cerebral blood flow assessment, histological examination of brain tissue, assay kits were used to detect lactate dehydrogenase(LDH) and neuron-specific enolase(NSE) activities in rat serum. ELISA assay kits was used to measure interleukin-1(IL-1) and interleukin-6(IL-6) levels, and Western blot and immunohistochemistry were conducted to detect the expression levels of cleaved caspase-3, caspase-8, and TNF-α proteins in rat brain tissue 14 days post-surgery. Results After cerebral ischemia-reperfusion treatment, MCAO resulted in abnormal neurological function in rats, significantly increased neurological function scoring index, obvious changes in cerebral tissue histomorphology and cerebral blood flow, significant upregulation of cleaved caspase-3, caspase-8, and TNF-α protein expression levels in brain tissue, and significant elevation of LDH, NSE, IL-1, and IL-6 levels in serum. Rats in the TFR 200 mg/kg group showed significantly reduced neurological function scoring, significant improvement in cerebral tissue pathological damage, decreased expression levels of cleaved caspase-3, caspase-8, and TNF-α proteins in brain tissue, as well as decreased levels of LDH, NSE, IL-1, and IL-6 in serum. Conclusion TFR may alleviate cerebral ischemic hypoxic injury by inhibiting the TNF-α/caspase-8/caspase-3 signaling pathway.