Chlorogenic acid (CA) is a natural plant-derived polyphenol compound that is widely present in beverages (coffee and tea), fruits (blueberry, apple, and mulberry), and medicinal plants (Lonicera japonica, Eucommia ulmoides, and Cichorium intybus). In recent years, CA has attracted extensive attention due to its various health benefits, such as anti-inflammatory, immunomodulatory, anti-obesity, anti-diabetes mellitus, and neuroprotection activities. Interestingly, the low bioavailability of CA corresponds to high bioactivity, which raises a key scientifi c question of how low bioavailability CA can achieve high biological activity. In this review, we highlight the gut microbiota as a key target for connecting the two by summarizing a large amount of evidence. Specifi cally, the composition and abundance of gut microbiota, its metabolites, intestinal immunity, barrier function and so on were all changed under different pathological conditions such as infl ammatory bowel disease, liver disease, kidney disease, cardiovascular disease, diabetes mellitus, obesity, etc. Conversely, these changes could be reversed by CA. In a word, CA could achieve pharmacological activity as well as health-protective effects by modulating intestinal immune and barrier function, gut microbiota composition, gut microbiota metabolites, and signaling pathways. This review provides new targets for the prevention and treatment of diseases by CA. Meanwhile, regulating the composition of the gut microbiota through natural products may be a potential strategy to achieve health protection.