This project contains the cardiac proteomic dataset generated from a mouse model of heart failure with preserved ejection fraction (HFpEF). Male C57BL/6J mice were subjected to a dual-hit HFpEF protocol consisting of a high-fat diet and L-NAME administration, whereas age-matched control mice received standard chow and normal drinking water. Left ventricular myocardial tissues were collected and analyzed using data-independent acquisition liquid chromatography-tandem mass spectrometry. The study was designed to characterize HFpEF-associated alterations in the cardiac proteome and to identify upstream regulators of metabolic and mitochondrial remodeling. Differentially expressed proteins were primarily associated with fatty acid metabolism, mitochondrial organization, energy homeostasis, oxidative stress, and pathological cardiac remodeling. Integrated analysis identified oxidative stress-responsive kinase 1 (OXSR1) as a candidate pathogenic regulator associated with mitochondrial dysfunction and metabolic remodeling in HFpEF myocardium.