Aim High density lipoprotein (HDL) has the functions of mediating reverse cholesterol transport and anti-oxidation, thereby inhibiting atherosclerosis. In the case of metabolic syndrome, diabetes, smoking, etc., HDL undergoes oxidative modification, and the activity of HDL-related enzymes decreases, resulting in weakened functions. Antioxidants such as vitamin E can reduce the oxidative modification of HDL and enhance the activity of HDL-related enzymes such as paraoxonase 1, but their long-term safety remains to be verified. Hydrogen molecule, as a novel antioxidant, plays a good role in a variety of oxidative inflammatory diseases. Our research group has been devoted to the research of hydrogen molecule and atherosclerotic cardiovascular disease, and found that hydrogen molecule can increase the plasma high density lipoprotein cholesterol level in animals and humans with metabolic syndrome and hypercholesterolemia, and enhance the activity of HDL-related enzymes and its mediated cholesterol efflux function. This article reviews the animal experiments and clinical trials of the biological effects of hydrogen molecule on HDL.