The presence of abnormal levels of reactive oxygen species (ROS) is a recognized pathological feature of inflammatory bowel disease (IBD). Therefore, the development of orally administered antioxidants with high antioxidative capacity and gastric acid tolerance for the treatment of IBD is of great significance. Here, we present the design and synthesis of a bimetallic ruthenium-cobalt (RuCo) nanosheet for the treatment of IBD. The Ru-Co atoms within the nanosheet structure exhibit significant electron transfer properties owing to their electronegativity feature. Density functional theory calculations indicate that the RuCo nanosheets have higher d-band centers than the corresponding Ru and Co metal monoliths, which increases the catalytic activity. Such RuCo nanosheets exhibit superoxide dismutase and catalase-like cascade enzyme activities and show robust stability in gastric fluid over a 4 h period when exposed to simulated gastric fluid, ensuring desirable retention of antioxidative activity. Cellular and animal studies show that RuCo nanosheets are capable of effectively reducing oxidative stress, preventing inflammatory responses triggered by an abnormal increase in ROS at intestinal sites, and thus protecting cells from inflammatory damages. This research presents a gastric-acid-stabilized antioxidative nanocatalytic platform for the efficient treatment of inflammatory diseases of the digestive system.