<p>Endothelial cell senescence represents a critical mechanistic driver in the initiation and progression of cardiovascular diseases. Senescent endothelial cells exhibit characteristic features, including cell cycle arrest—mediated primarily through the p53/p21 and p16 pathways—morphological transformations such as increased cell volume, elevated caveolin-1 expression, and loss of LaminB1, as well as activation of the senescence-associated secretory phenotype (SASP). The SASP facilitates the secretion of numerous inflammatory cytokines and chemokines, thereby fostering a state of chronic inflammation and contributing to tissue dysfunction. Key molecular regulators of endothelial senescence include transcription factors such as NF-κB and p53, along with the p38 MAPK signaling pathway, which collectively modulate inflammatory responses, cell cycle progression, and stress adaptation. This review offers a comprehensive and integrative perspective on endothelial senescence as a central element in cardiovascular pathophysiology. Its novelty stems from a systematic synthesis of classical pathways, including p53/p21 and p16, with more recently implicated players such as mammalian target of rapamycin (mTOR) signaling and associated microRNAs (miRNAs), accompanied by a focused examination of the SASP as a core pathological mechanism in chronic inflammation and vascular impairment. Moving beyond singular pathways, this work constructs a multidimensional framework that integrates cell cycle arrest, morphological changes, SASP activation, and transcriptional regulation to delineate a cohesive pathological sequence through which endothelial senescence promotes cardiovascular disease.</p> Graphical abstract <p></p>