Polyphenols are secondary metabolites of plants that have been widely interested in for their health benefits as antioxidant. In the last decade, a large number of clinical trials and epidemiological studies have shown that long-term consumption of polyphenol-rich diet protects against chronic diseases such as cancers and cardiovascular diseases. Current cardiovascular researches have also suggested an important role of gut microbiota and circadian rhythm in the pathogenesis metabolic and cardiovascular diseases. It is known that polyphenols can modulate the composition of core gut microbiota and interact with circadian clock. In the present article, we summarize recent findings, review the molecular mechanisms and the potential of polyphenol as a dietary supplement for regulating gut microbiota and circadian rhythm for the prevention of cardiovascular diseases, and discuss future research directions.