Ulcerative colitis (UC) is an idiopathic, chronic, and progressive inflammatory set of conditions that affects the colonic mucosa. Natural polyphenols are well documented for their excellent antioxidant properties and have obvious advantages in the strategy of anti-oxidation treatment of UC. However, the poor water solubility, low bioavailability, and unstable nature have hindered their clinical application. Therefore, we efficiently encapsulated bioactive polyphenol epigallocatechin gallate (EGCG) with poly(N-vinylpyrrolidone) (PVP) via reliable intermolecular hydrogen-bonded interactions, and conjugated polysaccharide chondroitin sulfate (CS) with excellent gastrointestinal stability and CD44 active targeting capability onto the surface to achieve targeted delivery (EPC). The obtained EPC system showed an average diameter of 54 nm, monodisperse size distribution, and negatively charged surface. In vitro studies demonstrated the obvious reactive oxygen species (ROS)-scavenging and anti-inflammatory abilities of the EPC system. After oral administration, EPC system localized in the inflamed colon and effectively alleviated the symptoms in dextran sulfate sodium salt (DSS)-induced UC mice. Specifically, the EPC system down-regulated the expression of inflammatory cytokines, up-regulated the expression of tight junction-associated proteins to restore intestinal barrier, and modulated the gut microbiota. This oral drug delivery system with a simple self-assembling process may pave new strategy for polyphenol-based therapy in UC.