With the advancement of science and technology, the living standards of human beings have continuously improved, but the incidence and mortality from atherosclerosis worldwide have also increased by year. Although interventional surgery and the continuous development of new drugs have significant therapeutic effects, their side effects cannot be ignored. Polydatin, an active ingredient isolated from the natural medicine Polygonum cuspidatum, has been shown to have a prominent role in the treatment of cardiovascular diseases. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory, regulating lipid metabolism and anti-oxidative stress. This article will review the pharmacological mechanism of polydatin in anti-atherosclerosis, the biological characteristics of Polygonum cuspidatum, the toxicology and pharmacokinetics of polydatin and will provide ideas for further research.