Effective control of plaque accumulation is an important strategy for reducing the risk of both localized oral health issues and systemic diseases associated with plaque. However, existing approaches for preventing plaque accumulation exhibit some limitations, such as insufficient compatibility with the oral microbiota and tissues, as well as inconvenience in their use. Herein, inspired by dental plaque, a new class of peptides featuring excellent anti-fouling performance is successfully developed. Our peptides consist of a salivary-acquired peptide with tooth surface-selective adhesion, a zwitterionic peptide with anti-adhesion property, and four proline residues that provide structural rigidity. We conduct a series of progressive experiments, including molecular dynamics simulation and assessments of the anti-fouling performance of our peptides on hydroxyapatite slices, human tooth enamel slices, and ex vivo human teeth. The results demonstrate that our peptides possess the abilities of rapid anchoring on tooth surfaces and effective inhibiting protein and bacterial adhesion. These characteristics enable our peptide to efficiently control plaque accumulation through rinsing or spraying while preserving the balance of the oral microbiota. These findings open an appealing avenue for the development of anti-fouling agents for controlling plaque accumulation on tooth surfaces.