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Background: MicroRNA-29a (miR-29a) is involved in regulating cerebral ischemia process, but its underlying mechanism is unclear. We previously showed that inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) pathway improves the neurological outcome and increases the expression of miR-29a in transient middle cerebral artery occlusion (tMCAO) animal model. This study investigated the role of miR-29a in cerebral ischemia and reperfusion injury after mechanical reperfusion.Methods: The intraluminal filament tMCAO model was established in male rats with 2 hour ischemia followed by reperfusion. The expression of miR-29a and NOX4 in the infarction core and peri-infarct cortex were quantified at 0, 3, 12, and 24 hour after reperfusion. Permanent MCAO model was also evaluated after 2 hour and 24 hour ischemia. Intravenous miR-29a agomir was delivered immediately after reperfusion. Infarct volume, brain water content, neurological score, blood-brain barrier damage, and levels of miR-29a and NOX4 were determined at 24-hour after cerebral ischemia.Results: MiR-29a levels in the infarction core and peri-infarct cortex were significantly decreased at 3 hours after reperfusion in tMCAO group compared with the sham-operated group. The decreased levels of miR-29a lasted for 24 hours after cerebral ischemia. Dual-luciferase reporter system showed that NOX4 was the direct target gene of miR-29a. Intravenous miR-29a agomir increased the expression of miR-29a and suppressed NOX4 up-regulation in both the infarction core and peri-infarct cortex at 24-hour after ischemia compared with the tMCAO group (all p<0.05). Intravenous miR-29a agomir reduced infarct volume (24.7% ± 4.0% versus 37.8% ± 7.5%, p<0.01) at 24-hour after ischemia compared to the tMCAO group. MiR-29a agomir attenuated brain edema and reduced reperfusion-induced blood-brain barrier breakdown, resulting in improved neurological outcome (all p<0.05).Conclusions: MiR-29a overexpression protects against cerebral ischemia and reperfusion injury via downregulating NOX4. Infusion of miR-29a agomir immediately after reperfusion represents a novel adjunctive therapeutic strategy to improve outcome after mechanical reperfusion for acute ischemic stroke.