Nanozymes are nanomaterials with enzyme-like activities, which have been developed for inflammatory disease therapy by reactive oxygen species (ROS) scavenging. The application of nanozymes in ulcerative colitis (UC) treatment not only inherits the merits of small molecular antioxidants (e.g., 5-aminosalicylic acid) to scavenge ROS but also achieves catalytic recycle instead of stoichiometric consumption. However, current therapies usually ignore the repair of mucosa, the first line of defense, whose damage increases the risk of infections. Herein, a multifunctional nanozyme hydrogel is designed and verified both as an ROS scavenger and a mucosal healing enhancer for UC therapy. The chitosan-coated CeO2 nanozyme (CCNZ) not only possesses excellent ROS-scavenging ability but also exhibits satisfactory antibacterial capacity. After gelation with alginate, the optimized CCNZ1:Alg1.5 nanozyme hydrogel exhibits multiple functions, including inflamed site targeting, supporting cell growth, ROS scavenging, and antibacterial activity, which alleviates UC better than a clinical medication 5-aminosalicylic acid by even a single-dose treatment. This study reveals that a nanozyme providing mucosal healing is promising for UC therapy with excellent potential for clinical application and enriches the nanozyme research of treatment for diseases.