Inflammatory bowel disease is an idiopathic chronic inflammatory condition of the gastrointestinal tract, closely associated with autophagy and pyroptosis. Nanoparticles, as small-diameter particles, play a unique role in disease research. In this study, a one-pot method was used to synthesize ZnO@Cu5.4O nanoparticles and characterize them. To simulate the inflammatory process of intestinal epithelial cells, a coculture system of NK cells and NCM460 cells was established. Proteomics and Western blot experiments were used to measure the expression levels of the relevant proteins. Notably, 0.5ZnO@Cu5.4O demonstrated a strong inhibitory effect on GSDMB, an effect not observed with ZnO or Cu5.4O alone. Proteins in the 0.5ZnO@Cu5.4O group were significantly enriched in the autophagy signaling pathway. 0.5ZnO@Cu5.4O was able to significantly promote the expression of IFN-gamma, IL-6, TNF-alpha, and IL-1beta in the NCM460 and NK cell coculture system and also exhibited a remarkable inhibitory effect on inflammatory factors and reactive oxygen species. In vivo experiments revealed that the median lethal dose of 0.5ZnO@Cu5.4O was 52.78 mg/kg. Furthermore, 0.5ZnO@Cu5.4O greatly alleviated the symptoms in a DSS-induced inflammatory bowel disease model. After treatment with 0.5ZnO@Cu5.4O, serum levels of IL-6 and TNF-alpha in mice were significantly reduced. These findings provide new insights into the therapeutic potential of 0.5ZnO@Cu5.4O for IBD.