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Ouabain preconditioning (OPC) initiated by low concentrations of the cardiac glycoside (CG) ouabain binding to Na/K-ATPase is relayed by a unique intracellular signaling and protects cardiac myocytes against ischemia/reperfusion injury. To explore more clinically applicable protocols based on CG properties, we tested whether the FDA-approved CG digoxin could trigger cardioprotective effects comparable with those of ouabain using PC, preconditioning and PostC, postconditioning protocols in the Langendorff-perfused mouse heart subjected to global ischemia and reperfusion. Ouabain or digoxin at 10 μmol/L inhibited Na/K-ATPase activity by approximately 30% and activated PKCε translocation by approximately 50%. Digoxin-induced PC (DigPC), initiated by a transient exposure before 40 minutes of ischemia, was as effective as OPC as suggested by the recovery of left ventricular developed pressure, end-diastolic pressure, and cardiac Na/K-ATPase activity after 30 minutes of reperfusion. DigPC also significantly decreased lactate dehydrogenase release and reduced infarct size, comparable with OPC. PostC protocols consisting of a single bolus injection of 100 nmoles of ouabain or digoxin in the coronary tree at the beginning of reperfusion both improved significantly the recovery of left ventricular developed pressure and decreased lactate dehydrogenase release, demonstrating a functional and structural protection comparable with the one provided by OPC. Given the unique signaling triggered by OPC, these results suggest that DigPostC could be considered for patients with risk factors and/or concurrent treatments that may limit effectiveness of ischemic PostC.