The diagnosis and therapy of heart failure with preserved ejection fraction (HFpEF) are complicated by the disease’s varied etiology. In the field of heart failure (HF), N-terminal pro-B-type natriuretic peptide (NT-proBNP) has become an important biomarker, providing information on diagnosis, prognosis, and treatment monitoring. This in-depth investigation looks at the connection involving NT-proBNP levels and HFpEF, offering information on possible diagnostic applications as well as consequences for patient care. The study reviews the literature on the connection concerning NT-proBNP and HFpEF and emphasizes how NT-proBNP aids in the distinction of HFpEF from various cardiac and non-cardiac conditions. HF is known to be associated with elevated NT-proBNP levels, but the complex link with HFpEF necessitates careful examination. The abstract explores the difficulties in using NT-proBNP as a diagnostic tool for HFpEF, taking into account the potential influence of renal function, age, and comorbidities on NT-proBNP levels. Additionally, the predictive importance of NT-proBNP in HFpEF is explored, emphasizing its capacity to forecast death and severe cardiovascular events. The abstract emphasizes that diagnosing HFpEF requires a multimodal approach that includes clinical assessment, imaging modalities, and NT-proBNP measurement. In order to accurately manage patients with HF, particularly HFpEF, the abstract highlights the significance of integrating clinical judgment and other diagnostic measures, even though NT-proBNP is still a useful marker in this regard. Lastly, the study offers suggestions for future research trajectories that should further our knowledge of NT-proBNP’s function in HFpEF and improve its clinical applicability in this intricate and varied illness.