Oral infectious diseases caused by a variety of pathogenic bacteria seriously affect the quality of life. However, these diseases remain a clinical challenge because of the lack of simple, safe, and universal prophylactics. To address these limitations, we synthesize CuOx nanodots (CuOx NDs) with excellent Fenton-like reaction activity and utilize them in the treatment of oral bacterial infections. Different from other complicated approaches, CuOx NDs are rationally prepared using a facile one-pot aqueous synthesis. In the presence of H2O2, these well-developed CuOx NDs can efficiently catalyze the generation of hydroxyl radicals (·OH) around oral pathogens, leading to the death of various bacteria. Meanwhile, results of biosafety indicate the high biocompatibility and extremely low toxicity of these CuOx NDs. After understanding the admirable in vitro antibacterial effect of CuOx NDs in the presence of H2O2, we further explore their in vivo antibacterial performance on several classical animal models including oral mucosal wound model, intragingival bacteria-infected model, and the periodontal infection model. As expected, these CuOx NDs with wide-spectrum antibacterial activity can serve as high-performance antibacterial reagents for the treatment of various oral bacterial infections with the help of H2O2. In brief, current nanoplatform can act as efficient antibiotics against oral pathogens with broadening the biomedical applications of copper-based nanomaterials.