Cerebral infarction causes severe social and economic burdens to patients due to its high morbidity and mortality rates, and the available treatments are limited. RO27-3225 is a highly selective melanocortin receptor 4 agonist that alleviates damage in many nervous system diseases, such as cerebral hemorrhage, traumatic brain injury and chronic neurodegenerative diseases. However, the effect of RO27-3225 on cerebral infarction remains unclear. In this study, we used a mouse model of transient middle cerebral artery occlusion (tMCAO) and administered RO27-3225 or saline to the mice through intraperitoneal injection. RO27-3225 increased the number of Nestin/BrdU cells and doublecortin (DCX)/BrdU cells in the subventricular zone (SVZ) and the number of DCX/BrdU cells in the peri-infarct area on day 7 after tMCAO. Furthermore, RO27-3225 decreased the number of activated microglia (Iba1 cells with a specific morphology) and the expression levels of Iba1, TNFα, IL6, and iNOS proteins and increased the number of PDGFRβ cells in the peri-infarct region on day 3 after tMCAO. Finally, RO27-3225-treated mice exhibited significantly decreased infarct volumes, brain water contents, and neurological deficits after cerebral infarction. Thus, RO27-3225 can improve the outcomes following cerebral infarction, partially by regulating neurogenesis in the SVZ, PDGFRβ cell survival and neuroinflammation in the peri-infarct zone. Our research reveals that RO27-3225 is a potential new treatment for cerebral infarction.