We have investigated whether acute (swimming) exercise is sufficient to have sustained beneficial effects against cardiac functional decline observed after high-dose isoproterenol administration. Mice were subjected to one bout of swimming for 30 min (“swim” group). Twenty-four hours later, they were given isoproterenol (160 mg/kg) to cause injury. Two control groups were included, a shallow “water” group, for which no swimming took place, and a “cage” group; they were both given isoproterenol as in the “swim” group. Cardiac function was assessed by tissue Doppler imaging (TDI) 24 h, 2 weeks, and 4 weeks post-isoproterenol. Left ventricular (LV) systolic function including endocardial velocity and radial strain rate declined significantly in all groups at all time points after isoproterenol, compared with their pre-isoproterenol treatment values. The “swim” group, however, had significantly higher LV systolic function compared with either of the control groups at 24 h, and this improvement persisted 2 and 4 weeks post-treatment. There were no significant differences between the control groups at any time point. In conclusion, a single bout of swimming has sustained beneficial effects against injury, as measured by TDI, after administration of isoproterenol.