Magnesium sulfate and nimesulide are commonly used drugs with reported neuroprotective effects. Their combination as stroke treatment has the potential benefits of decreasing individual drug dosage and fewer adverse effects. This study evaluated their synergistic effects and compared a low-dose combination with individual drug alone and placebo. Sprague-Dawley rats underwent 90 min of focal ischemia with intraluminal suture occlusion of the middle cerebral artery followed by reperfusion. The rats were randomly assigned to receive one of the following treatments: placebo, magnesium sulfate (MgSO₄; 45 mg/kg) intravenously immediately after the induction of middle cerebral artery occlusion, nimesulide (6 mg/kg) intraperitoneally before reperfusion, and combined therapy. Three days after the ischemia-reperfusion insult, therapeutic outcome was assessed by 2,3,5-triphenyltetrazolium chloride staining and a 28-point neurological severity scoring system. Cyclooxygenase-2, prostaglandin E₂, myeloperoxidase, and caspase-3 expression after treatment were evaluated using Western blot analyses and immunohistochemical staining, followed by immunoreactive cell analysis using tissue cytometry. Only the combination treatment group showed a significant decrease in infarction volume (10.93±6.54% versus 26.43±7.08%, p<0.01), and neurological severity score (p<0.05). Low-dose MgSO₄ or nimesulide showed no significant neuroprotection. There was also significant suppression of cyclooxygenase-2, prostaglandin E₂, myeloperoxidase, and caspase-3 expression in the combination treatment group, suggesting that the combination of the two drugs improved the neuroprotective effects of each individual drug. MgSO₄ and nimesulide have synergistic effects on ischemia-reperfusion insults. Their combination helps decrease drug dosage and adverse effects. Combined treatment strategies may help to combat stroke-induced brain damage in the future.