Diabetic wounds are among the most severe chronic complications in patients with diabetes. Owing to the detrimental effects of high glucose and high levels of reactive oxygen species (ROS) in the wound microenvironment, diabetic wound healing is significantly challenging. To address the issues of elevated ROS levels and infection susceptibility in diabetic wounds, we designed a composite hydrogel system loaded with cerium dioxide nanoparticles (CeO2 NPs) and vancomycin. This hydrogel aimed to reshape the wound microenvironment by continuously consuming ROS and inhibiting infection. Experimental results demonstrated that the CeO2 NPs-loaded hydrogel demonstrated an 85.40% clearance rate of hydroxyl radicals (·OH) and achieved over 90% inhibition against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), and effectively promoted the healing of diabetic mouse wounds. This cerium dioxide nanozyme hybrid hydrogel system can exert antioxidative and antibacterial effects and serve as a wound dressing to promote the healing of infected diabetic wounds.