Doxorubicin (DOX) is an anthracycline antibiotic routinely used as a chemotherapeutic agent for the treatment of solid tumours. However, DOX possesses an acute and cumulative cardiotoxicity due to free radical production. The present study was designed to investigate the possible protective effects of saffron (Crocus sativus) extracts against DOX-induced acute cardiotoxicity in isolated rabbit hearts submitted to 30 min global ischemia followed by 40 min reperfusion. DOX was delivered during reperfusion, without or with saffron given 5 min before ischemia or at reperfusion. Cardiodynamic, biochemical, and histopathological parameters were determined. In addition, to determine the expression of the AKT/mTOR/4EBP1 pathway, the levels of p38 MAPK and cardiac troponin T in heart homogenates were visualized by Western blotting. DOX administration during 40 min of reperfusion increased ischemic tissue damage, but did not act synergistically. Administration of saffron extracts during the first minutes of reperfusion significantly reduced oxidative myocardial damage, but was less effective when given before ischemia. Subsequent Western blot analysis revealed that saffron administration preserved cardiac troponin T proteins, inhibited the p38 MAPK pathway, and activated the AKT/mTOR/4EBP1 pathway in reperfusion- and DOX-treated rabbit hearts. In conclusion, saffron extracts, acting through antioxidant and antiapoptotic mechanisms, exhibited a protective effect against DOX-induced cardiotoxicity under ischemic condition.