Sex and aging represent important factors that determine morbidity and mortality due to cardiovascular diseases in the human population. This study aimed to investigate the impact of aging on the response to ischemia–reperfusion in male and female rat hearts, and to explore a potential role of the PI3K–Akt pathway in the cardioprotective effects of ischemic preconditioning (IPC) in the myocardium of younger and older adult males and females. Langendorff-perfused nonpreconditioned and preconditioned hearts of 12- and 18-week-old male and female Wistar rats were subjected to regional ischemia and reperfusion with or without prior perfusion with the PI3K inhibitor wortmannin for the evaluation of ischemia-induced arrhythmias and the size of myocardial infarction (infarct size; IS). Aging did not modify IS in both sexes; however, it markedly increased susceptibility to arrhythmias. Although IPC effectively reduced IS in males and females of both ages, only the hearts of males and 18-week-old females benefited from its antiarrhythmic effect. In the preconditioned 12-week-old females, but not the 18-week-old females, and in males of both ages, wortmannin blunted the anti-infarct effect of IPC. In conclusion, activation of the PI3K–Akt pathway plays an important role in protection against lethal injury conferred by IPC in males irrespective of age. The IS-limiting effect of IPC appears to be PI3K–Akt-dependent only in the 12-week-old females.