Hypertension-related fatigue involves both elevated blood pressure and reduced exercise tolerance, yet its molecular basis remains unclear. This study investigated the repositioning effects of spironolactone on hemodynamic and metabolic parameters in a uninephrectomy–deoxycorticosterone acetate-salt rat model of salt-sensitive hypertension. Male Sprague–Dawley rats were randomized to receive spironolactone (100 mg/kg/day) or vehicle (carboxymethylcellulose) for 5 weeks. Blood pressure was measured noninvasively, exercise capacity was assessed using a weighted swimming test, plasma sodium was quantified by enzyme-linked immunosorbent assay, and cardiac hypoxia-inducible factor 1 alpha (HIF-1α) expression was analyzed by quantitative polymerase chain reaction. Complementary in silico analyses included functional enrichment of spironolactone–HIF-1α targets, molecular docking with factor inhibiting hypoxia-inducible factor-1 (FIH1; PDB ID: 8II0), free energy calculations, and quantum mechanical assessment. Spironolactone prevented increases in systolic, diastolic, and mean arterial pressure, normalized plasma sodium levels, and suppressed cardiac HIF-1α expression. A non-significant trend toward prolonged time-to-fatigue was observed in spironolactone-treated rats. When interpreted alongside metabolic and hypoxia-related molecular findings, this trend suggests a potential antifatigue effect, although definitive conclusions cannot be drawn from the current dataset. Computational analyses identified HIF-1α and glycolytic pathways as central interaction hubs, with spironolactone demonstrating favorable binding to catalytic residues of FIH1, an asparaginyl hydroxylase, consistent with a mechanism that may enhance HIF-1α hydroxylation and attenuate hypoxia-driven glycolytic reprogramming in the hypertensive myocardium. These findings suggest that spironolactone exerts integrated hemodynamic and metabolic benefits and may hold therapeutic potential for hypertension-related fatigue, warranting confirmation in future studies or clinical translation in salt-sensitive populations. © 2026 Muhamad Rizqy Fadhillah et al.