Two-dimensional Bi2Se3 TIs were recently found to be the most promising room-temperature topological insulators for its relatively large bulk gap, but its surface frictional response is little investigated. Here, we prepared single-crystalline Bi2Se3 nanoplates with a lateral dimension up to ~ 1 μm and a thickness of less than 200 nm via a simple polyol method, and the molecular structure and morphology were characterized in detail using different methods. The micro-frictional behavior of Bi2Se3 nanoplates with different thickness is inventively investigated with AFM technique. The atomic stick–slip friction stemming from periodic crystal lattice, and the larger friction force of thinner nanoplates is attributed to the larger adhesion force and enhanced energy dissipation. This work has, for the first time, built the link of the behavior of topological protected surface and mechanical friction behavior of Bi2Se3.