<p>Piezo1, a mechanosensitive cation channel characterized by its distinctive transmembrane trimeric structure, plays a pivotal role in mediating cellular responses to mechanical stimuli. It facilitates calcium influx, and recent studies highlight its involvement in heart failure (HF) pathophysiology, where its dysregulation significantly contributes to disease progression. Specifically, Piezo1 upregulation impacts diverse cellular processes across cardiovascular cell types, including cardiomyocytes, fibroblasts, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs). Unlike previous studies that have focused predominantly on isolated signaling pathways, this review offers a comprehensive examination of Piezo1’s mechanosensory functions across diverse cardiovascular cell populations. We explored how Piezo1 modulates key pathological processes in heart failure, including calcium homeostasis, reactive oxygen species (ROS) production, fibrosis, vascular remodeling, and immune activation. Furthermore, we investigated how Piezo1-mediated interactions between different cell types, such as cardiomyocyte–fibroblast crosstalk and endothelial–smooth muscle cell interactions, serve as critical drivers of disease progression. Additionally, we discuss the therapeutic potential of targeting Piezo1, suggesting that modulating its activity may offer a novel strategy to mitigate the pathological effects of heart failure. By providing new insights into the multifaceted roles of Piezo1, this review highlights the potential of mechanosensitive ion channels as therapeutic targets for cardiovascular disease.</p> Graphical abstract <p></p>