The incidence and prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) continue to rise, yet evidence-based therapy remains limited. Due to the complexity of HFpEF pathology, traditional HF medication has shown inconsistent efficacy in improving clinical outcomes and reducing morbidity. Therefore, highlighting the urgent need for novel interventions. The αlpha-7 nicotinic acetylcholine receptor (α7nAChR) is a central mediator of the cholinergic anti-inflammatory pathway and has emerged as a promising therapeutic target in various conditions, such as sepsis, arthritis, metabolic dysfunction, and atherosclerosis. This review aims to examine the emerging therapeutic potential of α7nAChR in HF and HFpEF pathology, focusing on its protective role in modulating the complex interplay between systemic and cardiovascular inflammation, renin-angiotensin-aldosterone system activation, neurocardiac signaling and metabolic dysfunction.