Most current lattice Boltzmann (LBM) models suffer from the deficiency that their parameters have to be obtained by fitting experimental results. In this paper, we propose a new method that integrates the molecular dynamics (MD) simulation and LBM to avoid such defect. The basic idea is to first construct a molecular model based on the actual components of the rock–fluid system, then to compute the interaction force between the rock and the fluid of different densities through the MD simulation. This calculated rock–fluid interaction force, combined with the fluid–fluid force determined from the equation of state, is then used in LBM modeling. Without parameter fitting, this study presents a new systematic approach for pore-scale modeling of multi-phase flow. We have validated this approach by simulating a two-phase separation process and gas–liquid–solid three-phase contact angle. Based on an actual X-ray CT image of a reservoir core, we applied our workflow to calculate the absolute permeability of the core, vapor–liquid H2O relative permeability, and capillary pressure curves.