AbstractContext Styrax is used for prevention and treatment of cerebrovascular diseases. However, the underlying mechanism remains unclear.Objective To elucidate styrax’s anti-ischemic stroke protective effects and underlying mechanisms.Materials and methods An ischemic-stroke rat model was established based on middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were randomly assigned to the following groups (n = 10) and administered intragastrically once a day for 7 consecutive days: sham, model, nimodipine (24 mg/kg), styrax-L (0.1 g/kg), styrax-M (0.2 g/kg) and styrax-H (0.4 g/kg). Neurological function, biochemical assessment, and ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS)-based serum metabonomics were used to elucidate styrax’s cerebral protective effects and mechanisms. Pearson correlation and western blot analyses were performed to verify.Results The addition of 0.4 g/kg styrax significantly reduced cerebral infarct volume and neurobehavioral abnormality score. Different doses of styrax also decrease MDA, TNF-α, IL-6, and IL-1β, and increase SOD and GSH-Px in ischemic-stroke rats (p