Ferroptosis has been closely linked to the pathological processes of various diseases, making it a promising target for therapeutic intervention. Understanding the regulatory mechanisms underlying ferroptosis and developing effective pharmacological strategies is essential. Nanomedicine, particularly the use of nanozymes, offers a potential approach for regulating ferroptosis. In this study, we investigated the inhibitory activity of ultra-small, biocompatible cerium oxide nanoparticles (CeO NPs) on ferroptosis and explored the underlying molecular mechanisms. CeO NPs exhibited potent superoxide dismutase (SOD) and catalase (CAT) activities, efficiently scavenging multiple free radicals and lipid peroxidation products both intracellularly and extracellularly. These activities effectively prevented or alleviated ferroptosis in RSL3-induced cells. Proteomic analysis revealed that CeO NPs significantly altered the expression of numerous proteins, including a reduction in pro-inflammatory cytokines. Mechanistically, CeO NPs specifically regulated the expression of key proteins involved in ferroptosis-related metabolic processes, reducing iron accumulation and lipid peroxidation, and thereby decreasing cellular susceptibility to ferroptosis. Our findings demonstrate that CeO NPs synergistically inhibit ferroptosis by both scavenging reactive oxygen species (ROS) and modulating the expression of ferroptosis-regulating proteins. In conclusion, this study highlights the potential of CeO NPs as a promising nanozymes for ferroptosis inhibition, offering novel insights into the design of CeO NPs-based therapies for ferroptosis-related diseases.