Chemo-mechanical grinding (CMG) is a valid processing method to achieve a low-damage surface of silicon. However, the atomic interfacial mechanism during the CMG is still unclear. Herein, the CMG process of silicon was investigated using first principles and frictional wear tests in which the effects of pressure and speed on the interfacial reaction were comprehensively analyzed. Simulations showed that the formation and breakage of chemical bonds occurred at the CeO2/silicon interface during CMG, and the newly formed chemical bonds were stronger than those on the silicon surface. Also, it was found that the pressure and speed improved the materials removal rate by means of accelerating the interfacial chemical reactions, which is also verified by frictional wear tests. This study provides new insights into the atomic interfacial mechanism during silicon CMG.