Oxidative stress leads to intestinal barrier damage, which induces immune responses to occur and further promotes oxidative stress exacerbating inflammatory bowel disease (IBD). In this work, the multifunctional Zn(x)Ce(y)O(2)/Se (ZCSO) nanozyme wrapped with acid-resistant calcium alginate hydrogel designed for oral administration is prepared. The ZCSO nanozyme can promote the activation of the Nrf2 oxidative stress pathway, then significantly improve the efficiency of scavenging reactive oxygen species (ROS) and up-regulate the protein expression of glutathione peroxidase 4 (GPx4), which is closely related to the inhibition of ferroptosis. In addition, the ZCSO nanozyme inhibiting the growth of some pathogenic bacteria proliferating due to oxidative stress shows a positive regulation of the intestinal flora and reduces the secretion of pro-inflammatory factors and the levels of inflammatory macrophages, achieving the significant preventive and delayed therapeutic effect of colitis mice. Consequently, the distinctive properties of ZCSO nanozyme render it a promising candidate for the treatment of IBD by effectively scavenging ROS, thereby interrupting the detrimental cycle between oxidative stress and immune response, ultimately promoting the proliferation of epithelial cells to reestablish the integrity of the intestinal mucosal barrier.