Although synergistic therapy for diabetes mellitus has displayed significant promise for the effective treatment of diabetic nephropathy (DN), developing a simple and effective strategy to construct multifunctional nanoparticles is still a huge challenge. Moreover, the complicated pathological mechanism of DN involves various pathway dysfunctions that limit the effectiveness of a single therapeutic approach. Herein, hollow mesoporous silica nanocomposite (HMSN) particles doped with trace cerium oxide that exhibit renoprotective activity have been designed, which not only have the ability to prevent ROS-associated DN pathogenesis but also have high drug loading capacity. Interestingly, the metformin (MET) loaded multifunctional nanoparticles (MET–HMSN–CeO₂) with a special size exhibited significantly increased kidney accumulation over free MET. Moreover, the cyclic conversion between Ce³⁺ and Ce⁴⁺ of mixed-valence ceria in our system provides the possibility for long-term ROS-scavenging activity to achieve the antioxidative effect. Then, we investigated the renoprotective effect of these nanoparticles on the streptozotocin (STZ)-induced renal injury rat model and high-glucose induced NRK-52E cell damage model. As a result, our findings demonstrated that the nanoparticles could alleviate the DN symptoms by mitigating oxidative stress, suppressing cellular apoptosis and protecting renal injury both in vitro and in vivo. The kidney deficits of DN are significantly improved after treatment with MET–HMSN–CeO₂. Overall, our studies indicated that the MET–HMSN–CeO₂ multifunctional nanoparticles would be a promising therapeutic candidate for DN.