Sedentary behavior has emerged as a major independent risk factor for cardiovascular diseases (CVDs), distinct from the lack of moderate-to-vigorous physical activity. With rapid technological advancements, urbanization, and increased screen-mediated occupations, prolonged sitting has become a dominant feature of modern lifestyles across all age groups. This systematic review synthesizes global evidence on the association between sedentary behavior and the risk of cardiovascular morbidity and mortality. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases for studies published between 2000 and 2024. A total of 71 studies, including cohort studies, randomized trials, and meta-analyses, were included after PRISMA-guided screening. The findings consistently demonstrate that prolonged sedentary time is associated with increased risks of coronary artery disease, hypertension, heart failure, stroke, and cardiovascular mortality, independent of traditional physical activity levels. Mechanistically, sedentary behavior contributes to endothelial dysfunction, chronic inflammation, autonomic imbalance, insulin resistance, dyslipidemia, and visceral adiposity. Vulnerable populations—including the elderly, individuals with metabolic disorders, and office-based workers—exhibit heightened susceptibility. The review further highlights that breaking up sedentary time with light-intensity activity significantly reduces cardiovascular risk. These findings emphasize the urgent need to integrate sedentary behavior reduction into cardiovascular prevention strategies alongside physical activity promotion, occupational health policies, and digital lifestyle interventions.