Aim To investigate the protection effect of microRNA-22 on cardiac function and ventricular remodeling after myocardial infarction. Methods The study constructed mouse myocardial infarction model and transfected adenovirus containing microRNA-22 into peri-infarct area. It assessed cardiac function four weeks after myocardial infarction by using echocardiography. Mouse exercise ability was assessed by swimming. HE and Masson staining was applied to assess microstructure and fibrosis of myocardium. Results Over-expressing of microRNA-22 improved mouse left ventricular ejection fraction (LVEF) percentage (49.38%±2.51% vs 42.29%±2.74%, P<0.05) and fractional shortening (FS) percentage (24.24±0.64% vs 22.59%±0.73%, P<0.05) compared with adeno-null group. Mouse in adeno-microRNA-22 group showed longer swimming time and better exercise ability (8.13±1.01 min vs 7.02±1.32 min, P<0.05).HE and Masson staining also showed better cardiac microstructure and less fibrosis. Adeno-microRNA-22 group showed elevated microRNA-22 expression (6.66±2.01 vs 1.22±0.07, P<0.05) and down-regulated PTEN protein expression (0.63±0.19 vs 2.23±0.44, P<0.05). Conclusion Over-expression of microRNA-22 protected mouse cardiac function and reduced ventricular remodeling after myocardial infarction.