Inflammatory bowel disease (IBD) is a refractory chronic inflammatory disease. An excessively high level of reactive oxygen species (ROS) in the colon is one of the characteristics and pathogenic factors of IBD. Therefore, scavenging excessive ROS is a feasible method to treat IBD. Because ROS include many types of species, scavenging a single kind of ROS is not enough to reduce the ROS level and cure IBD effectively. Herein, broad-spectrum ROS scavenging and activated macrophage-targeting microparticles (MPs) are successfully fabricated by coprecipitation of catalase (CAT) and bovine serum albumin into a MnCO3 template followed by deposition of polydopamine (PDA), assembly of targeting molecules on the surface, and finally removal of MnCO3. The CAT content of MPs is about 34.1%. The obtained MPs can effectively scavenge the broad spectrum of ROS and retain 88% of the radical scavenging activity even after the treatment of simulated gastric fluid. The surface-modified dextran sulfate endows MPs with the targeting ability toward activated macrophages, achieving a better therapeutic effect. The MPs with components mostly derived from natural substances exhibit good biocompatibility and can show excellent ROS scavenging ability in cell experiments. In animal experiments, oral administration of a proper dosage of MPs can substantially mitigate colonic inflammation, as evidenced by disease activity index scores reduced by similar to 40%, reduced body weight loss, and the production of typical proinflammatory cytokines in the inflammatory colon. This kind of MP can also be utilized for the treatment of other inflammatory diseases.