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Salidroside (SAL), an antioxidant derived from Rhodiola rosea, exerts neuroprotective effects in cerebral ischemia/reperfusion (I/R) injury; however, the mechanisms have not been fully elucidated. The present study established a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a cellular model of oxygen–glucose deprivation/reoxygenation (OGD/R) to explore the roles and mechanisms of SAL in cerebral I/R injury. The rat model of MCAO/R was established and rats were treated with different doses of SAL. The Zea-Longa scoring system and 2,3,5-triphenyltetrazolium chloride (TTC) staining showed that SAL reduced neurological deficit scores and cerebral infarct volumes in MCAO/R rats. The results of Morris water maze (MWM) test showed that SAL reduced memory impairment in MCAO/R rats. In addition, SAL significantly reduced oxidative stress and suppressed inflammatory response. Next, the OGD/R model was established with PC12 cells and treated with SAL. The results of flow cytometry and 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays showed that SAL reduced apoptosis, enhanced cell viability and protected neuronal cells from damage by decreasing lactate dehydrogenase (LDH) activity. SAL increased the expression of TSC complex subunit 2 (TSC2), and activated the 5′-AMP-activated protein kinase (AMPK) and inhibited the mammalian target of rapamycin (mTOR) signaling pathways. It was verified that SAL alleviated cerebral I/R injury by regulating the AMPK/TSC2/mTOR pathway to induce autophagy. In conclusion, SAL reduces the inflammatory response and oxidative stress in a concentration-dependent manner, and protects against cerebral I/R injury by modulating TSC2-induced autophagy. These findings suggest SAL may prove to be a potential therapeutic agent for ischemic stroke. [ABSTRACT FROM AUTHOR]