Artificial nanomotors are undergoing significant developments in several biomedical applications. However, current experimental strategies for producing nanomotors still have inherent drawbacks such as the requirement for expensive equipment, strict controlling of experimental conditions, and strenuous processes with several complex procedures. In this study, we describe for the first time a facile single-step thermodynamic-controlled coating method to prepare Janus mesoporous organosilica nanomotors. By controlling the total free energy of organosilica oligomers (G) from a low development level to a high level in the reaction system, the nonspontaneous nucleation on the platinum (Pt) nanosurface and the spontaneous nucleation in a solvent can be controlled, respectively. More importantly, we reveal that the molecular arrangement and contact angle of deposited organosilica on Pt cores vary with the total free energy of organosilica oligomers (G). Different values of θ would change the trend of detachment from Pt for organosilica nucleated cores and carry out diverse coating modes. These are indicated by the morphology evolution of platinum/organosilica hybrids, from naked platinum nanoparticles, evenly distributed organosilica shell/core, nonconcentric to typical Janus nanomotor. The prepared Janus mesoporous nanomotor (JMN) showed typical mesopore structures and active propelling behaviors under H2O2 stimulation. In addition, the JMN modified with hyaluronic acid exhibited excellent biocompatibility and improved tumor penetration under H2O2 stimulation. The successful construction of other nanomotor frameworks based on a gold-templated core proves the perfect applicability of the thermodynamic-coating method for the production of nanomotors. In conclusion, this work establishes a manufacturing methodology for nanomotors and drives nanomotors for promising biomedical applications.