Impaired coronary microvascular function (e.g., reduced dilation to physiological stimuli and decreased coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether this results from improved regulation of coronary resistance, a process dependent on voltage-dependent K+ (Kv) channel activation, or reduced coronary structural remodeling is unclear. Indeed, recent evidence suggests MR-dependent regulation of vascular K+ channels and pathologic stiffening. Thus, the goals of this investigation were to determine: 1) the effects of obesity on coronary vasodilation to graded reductions in arterial PO2; 2) the contribution of Kv channels to hypoxemic coronary vasodilation; and 3) whether chronic MR blockade improves hypoxemia-induced coronary vasodilation in obesity and underlying mechanisms. Hypoxemia increased coronary blood flow to a similar degree in lean and obese swine, however coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, or restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of alterations in Kv channel function.