We investigated the effects of voluntary wheel running prior to an acute myocardial infarction (MI) on survival, left ventricular (LV) remodeling and dysfunction, and whether exercise prior and after MI provides superior protection compared to either exercise intervention alone. After 2-weeks of voluntary wheel running or sedentary housing, MI was induced in C57Bl/6 mice after which exercise stopped (EX-MI-SED, SED-MI-SED) or continued (EX-MI-EX, SED-MI-EX) for a period of 8-weeks. Exercise after MI in SED-MI-EX mice had no effect on survival, the area of infarction and global LV remodeling, but attenuated fibrosis and apoptosis in remote myocardium and blunted LV dysfunction and pulmonary congestion, compared to SED-MI-SED mice. Exercise prior to MI in both EX-MI-SED and EX-MI-EX mice decreased post-MI mortality compared to both SED-MI-SED and SED-MI-EX mice. Furthermore, in both pre-MI exercise groups the infarct-area was thicker, while interstitial fibrosis and apoptosis in the remote LV myocardium were blunted. In contrast, the ameliorating effects of either pre-MI or post-MI exercise alone on LV dysfunction were lost in EX-MI-EX mice, which may in part be related to the increased daily exercise distance in the first week post-MI in EX-MI-EX versus SED-MI-EX mice. In conclusion, exercise prior to or after MI blunted LV dysfunction, whereas only exercise prior to MI improved survival. These findings suggest that even when regular physical activity fails to prevent an acute MI it can still act to improve cardiac function and survival after MI.