Inflammatory bowel disease (IBD) is related to excessive reactive oxygen species (ROS) and high expression of proinflammatory cytokines. An enzymatically active drug carrier that can simultaneously scavenge excessive ROS and deliver anti-inflammatory drugs to inhibit the production of inflammatory cytokines may lead to improved therapeutic effects. Herein, nanoparticles (NPs) that can target activated macrophages, remove ROS and release anti-inflammatory drugs are fabricated by loading budesonide (Bud) into dextran sulfate sodium (DSS)-coated hollow mesoporous manganese dioxide (hMnO2) NPs. This strategy can treat IBD better through the synergistic effect of the ROS-scavenging hMnO2 carriers and anti-inflammatory drug by blocking the amplification effect of inflammation. In addition, compared with free Bud, the drug delivery system can reduce side effects of Bud and improve its treatment outcome at the same dosage. Therefore, this study provides a new method for the design of highly effective synergistic anti-inflammatory nanomedicines.