Summary: Aims: Manganese superoxide dismutase (MnSOD), one of the most crucial antioxidant enzymes in the central nervous system, is thought to be one of the major mechanisms by which cells counteract the injuries of reactive oxygen species after cerebral ischemia. In this study, we used a novel synthesized compound (MnTm4PyP) with highly effective superoxide dismutase activity to study the therapeutic potential of MnSOD and the possible underlying mechanisms in cerebral ischemia.Methods: Primary cultured cortical neurons were used to examine the protective effect of the compounds. Mice with middle cerebral artery occlusion were used as ischemic stroke animal model. Animals were pretreated with MnTm4PyP intravenously 30 min before surgery. At 24 h after surgery, neurological behavior and histological function were observed. Infarcted cortex tissues and cultured neurons were collected for investigation of the oxidative stress signaling pathways.Results: In vitro studies revealed that MnSOD mimic MnTm4PyP pretreatment significantly increased viability of neurons after injury by H₂O₂. Intracellular superoxide radical levels were eliminated. In vivo experiments demonstrated MnTm4PyP pretreatment reduced infarct volume and improved neurological function. The MnSOD mimic alleviated oxidative stress and apoptosis.Conclusion: MnSOD is an effective therapeutic target in ischemic stroke prevention because of its antioxidant effects and oxidative stress regulation.