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Plant polyphenols are the main category of natural active substances, and are distributed widely in vegetables, fruits, and plant-based processed foods. Polyphenols have a beneficial performance in preventing diseases and maintaining body health. However, its action mechanism has not been well understood. Foodomics is a novel method to sequence and widely used in nutrition, combining genomics, proteomics, transcriptomics, microbiome, and metabolomics. Based on multi-omics technologies, foodomics provides abundant data to study functional activities of polyphenols. In this paper, physiological functions of various polyphenols based on foodomics and microbiome was discussed, especially the anti-inflammatory and anti-tumor activities and gut microbe regulation. In conclusion, omics (including microbiomics) is a useful approach to explore the bioactive activities of polyphenols in the nutrition and health of human and animals.