Background: The cerebral ischemic stroke befalls in response to the abrupt occlusion of blood vessels that leads to deprived oxygen and glucose in brain and causes brain injuries. Stroke is associated with higher morbidity and mortality rate globally. Syringin is a bioactive compound from Eleutherococcus senticosus and possesses plentiful biological actions. Objectives: In this research work, we envisioned to observe the neuroprotective actions of syringin against ischemic-reperfusion (I/R)-provoked ischemic stroke in rats. Materials and Methods: The focal cerebral I/R injuries were roused to the male Wistar rats through the middle coronary artery occlusion (MCAO) technique. The syringin (10, 25, and 50 mg/kg) was administered to the rats through intragastric route for 7 successive days prior to MCAO and another 3 days after MCAO. Sham rats were administered with usual diet. The neurological score and parameters were measured by standard methods. The status of inflammatory cytokines and mediators in both serum and brain tissues was considered by commercial assay kits. The mRNA expression of toll-like receptor (TLR) 4, MyD88, Fas, and FasL was inspected by reverse transcription–polymerase chain reaction technique. Results: The syringin administration to I/R rats established the lessened neurological score and parameters. Syringin supplementation was meritoriously suppressed the levels of the inflammatory cytokine, i.e., interleukin (IL)-1 β, IL-6, and tumor necrosis factor-α and enhanced the IL-10 status in I/R rats. Syringin abridged the inflammatory mediators like cyclooxygenase-2, prostaglandin-2, and nuclear factor kappa B levels in the serum and brain tissues. The mRNA expression of TLR4, MyD88, Fas, and FasL was noticeably downregulated by the syringin. Conclusion: Taken together, our results showed the curative role of syringin against ischemic stroke in rats. Syringin can be an auspicious anti-stroke agent in future to treat ischemic stroke.