The effective stress principle is the fundamental theory of soil mechanics. The effective stress transmitted between particles dominates the mechanical properties of soil, such as strength, deformation, and drainage. However, there remains a paucity of research on the effective stress in the compression of nano-scale clay minerals. This study explored the application of the effective stress principle in the consolidation behavior of kaolinite through the Molecular Dynamics method. The calibration and correction for micro effective stress and pore water pressure were first proposed. Micro-effective stress is the stress on the mineral itself in the contact part of two particles, while micro-pore water pressure always represents that on the weakly bound and free water in the same part. The strongly bound water film between particles can indirectly transmit the micro-effective stress through the electrical double-layer repulsion. The calculation of micro stress has been corrected according to the derivation of macro theory, and the results obtained corresponded well with that in the macro experiment. Moreover, the evolution of effective stress was analyzed by observing the interparticle water film. The increase in effective stress during consolidation was mainly due to the compression of the strongly bound water and the drainage of weakly bound and free water.