Background: As plant secondary metabolites, polyphenols have gained more attention with increasing market demand due to their potential benefit for health. However, the low uptake rate and target delivery efficiency of polyphenols towards target sites such as organs, tissues and cells limit their applications. Polyphenols possess binding affinities with proteins via non-covalent and (or) covalent interactions, which provide a strategy for engineering as polyphenol-protein complexes to protect them from oxidation and enzymatic hydrolysis during gastrointestinal digestion. Polyphenol engineering via polyphenol-protein interaction changes the physical and chemical characteristics of polyphenols, thereby protecting polyphenols from oxidation and enzymatic hydrolysis during gastrointestinal digestion and improving their uptake rate, target specific delivery and biological activity. Scope and approach: This review aims to describe the mechanisms underlying engineering polyphenols via polyphenol-protein interaction, as well as their effect on the antioxidative, anti-inflammatory and anti-cancer activities of polyphenols. Especially, it focuses on polyphenols functional enhancement for improved intestinal health by engineering with proteins. Key finding and conclusions: Polyphenol stability in gastrointestinal tract, uptake, target specific delivery, bioavailability and biological activity can be enhanced by engineering with proteins via polyphenol-protein interactions. The potential applications of the engineering polyphenol-protein complex for health benefit are specifically addressed, but their safety needs to be assessed carefully before developing as functional food ingredients.