Heart failure with preserved ejection fraction (HFpEF) is a major healthcare problem affecting approximately 1–2% of the adult population in highly developed countries. It is a heterogeneous condition with cardiometabolic disorders such as obesity, insulin resistance, diabetes mellitus, and hypertension. Pathophysiologically, HFpEF is currently recognized as a systemic disease characterized not only by impaired left ventricular relaxation and increased ventricular stiffness but also by chronic inflammation, endothelial dysfunction, myocardial fibrosis, and multi-organ involvement. This study aims to investigate the role of metabolic organ crosstalk and nutritional modulation in different HFpEF phenotypes. This review analyzes the current literature to investigate the interactions between the heart, adipose tissue, liver, and spleen in the pathophysiology of HFpEF. Chronic low-grade inflammation and adipose tissue dysfunction play central roles in the progression of HFpEF by activating the immune system, favoring ectopic lipid accumulation, and exacerbating fibrosis. The identification of specific HFpEF phenotypes (e.g., obesity-related versus aging-related) requires the application of distinct nutritional strategies that target metabolic inflammation and organ crosstalk, which may improve both myocardial and systemic function. HFpEF is a complex systemic disorder that requires phenotype-specific therapeutic approaches. Precision nutrition based on specific biomarkers, together with comprehensive cardiovascular management, may enhance therapeutic efficacy and complement pharmacological treatment in patients with HFpEF.