Accumulating evidence suggests that ischemia–reperfusion-induced injury is associated with the formation of reactive oxygen species (ROS). This study demonstrates the therapeutic effectiveness of novel europium-doped cerium oxide nanoparticles (Eu-doped Ceria NPs) as ROS scavengers in a mouse model of intestinal ischemia–reperfusion-induced injury. An increased production of superoxide radicals is detected in the intestine throughout the ischemia stage and again after initiating reperfusion. These changes in superoxide radical formation are associated with the induction of inflammatory cytokines in the intestine. This study further shows that Eu-Ceria NPs exhibit superoxide scavenging activity in vitro. Importantly, administration of Eu-Ceria NPs into the intestinal lumen during the onset of ischemia effectively blocks superoxide accumulation, reduces the expression of IL-1b, and ameliorates the intestinal pathology. These results suggest that early increased production of ROS during the ischemia–reperfusion promotes intestinal pathology and that mucosal delivery of Eu-Ceria NPs may be a potential therapeutic approach to block ROS accumulation and ameliorate the severity of intestinal disease.