Designing metal-metal oxide heteronanostructures with synergistic and superior activities (unattainable in the case of a single entity) is of great interest for a wide range of technological applications. Traditional synthetic strategies typically require reducing agents, stabilizing ligands, or high temperature reductive treatment to produce oxide-supported metals. Herein, a facile noble metal deposition strategy is developed to produce silver, gold, and platinum nanocrystals on the surface of hollow mesoporous cerium oxide nanospheres without any pretreatment. Unlike the galvanic replacement reaction, the developed protocol employs the innate reductive potential of CeO to produce a high density of ultrafine noble metal nanocrystals homogeneously immobilized onto the surface of CeO nanospheres. The multienzyme-like activities (i.e., superoxide dismutase-like and catalase-like) of CeO@metal nanostructures, originating from CeO and metal nanoparticles, were effectively utilized for anti-inflammatory therapies in two models. This oxygen vacancy-mediated reduction strategy can be generalized to produce diverse metal-metal oxide nanostructures for a wide range of applications.