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 tis-sue,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 West-ern 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 treat-ment,MCAO resulted in abnormal neurological function in rats,significantly increased neurological function sco-ring 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 neu-rological 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.