Klotho is an important endogenous pluripotent protein involved in pathophysiological processes such as aging and calcium/phosphorus metabolism, which is closely correlated with cardiovascular diseases. Recent clinical studies have found that low levels of Klotho expression are associated with more cardiovascular risk factors and predict cardiovascular risk; Basic studies have also shown that Klotho plays a pivotal role in maintaining vascular homeostasis and heart function. Klotho can promote nitric oxide (NO) production, reduce the expression of inflammatory factors and adhesion molecules, mediate the biological effects of anti-oxidation, anti-apoptosis, and anti-aging, alleviate atherosclerosis and vascular calcification, and inhibit cardiac hypertrophy and fibrosis. Klotho may serve as a new interventional target and provide new insights for the prevention and treatment of cardiovascular diseases. This review aims to summarize the association of Klotho with cardiovascular diseases and its underlying biological mechanisms.