Ulcerative colitis (UC) is defined as a chronic intestinal inflammation with an unknown cause. During its occurrence and development, oxidative stress and intestinal microbiota dysbiosis play important roles. Nevertheless, the treatment of UC continues to pose significant challenges due to the intricate nature of physiological barriers and the suboptimal targeting efficacy of traditional therapeutic strategies. To solve the dilemma facing UC treatment, in this study, we developed a metal-phenolic nanozyme, designated as DHM-Zn, which exhibits anti-inflammatory and antioxidant properties via metal coordination between dihydromyricetin (DHM) and Zn2+. Furthermore, we engineered yeast microcapsules (YM) encapsulating the metal-phenolic nanozymes (DZ@YM), leveraging the inherent biosafety and tolerability advantages offered by natural microorganisms. Following oral administration, the intestinal retention characteristics of YM facilitated the efficient aggregation of DHM-Zn nanozymes at the inflammation site, thereby extending their therapeutic efficacy. In addition to augmenting anti-inflammatory and antioxidant effects, DZ@YM contributed to the restoration of intestinal microbial balance by increasing the abundance of beneficial bacteria such as Parabacteroides and Muribaculaceae, while regulating potentially harmful bacteria like Clostridium-sensu-stricto and Escherichia-Shigella, thereby achieving a synergistic multi-pathway therapeutic approach. Collectively, with excellent biocompatibility, this novel therapeutic approach demonstrates extensive potential for clinical application in the treatment of UC and offers new directions and insights for UC therapy.