Heart mitochondrial ATP-sensitive potassium channels (mito-K ATP channels) are deeply implicated in the self-defense mechanism of ischemic preconditioning. Therefore, exogenous molecules activating these channels are considered as a promising pharmacological tool to reduce the myocardial injury deriving from ischemia/reperfusion events. This paper reports the synthesis and pharmacological evaluation of original spiromorpholine- and spiromorpholone-benzopyran derivatives, with the aim to obtain selective activators of mito-K ATP channels. Some compounds of this series showed appreciable cardioprotective effects on rat isolated and perfused hearts, submitted to ischemia/reperfusion cycles. The selective mito-K ATP channel blocker 5-hydroxydecanoic acid antagonized the anti-ischemic activity, indicating a clear implication of this pharmacological target. Furthermore, these effects were not associated with significant hypotensive and vasorelaxing properties, which represent one of the main limiting factors for the clinical use of nonselective K ATP-openers against myocardial ischemia.