Membrane distillation (MD) can utilize low level thermal energy and holds high potential to replace conventional energetically intensive separation technologies. Direct contact membrane distillation (DCMD) is suitable for the applications of desalination and concentration of aqueous solutions. Employing spacer-filled channels can enhance the mass flux of the DCMD modules, which can further result in the increase of energy utilization efficiency of the separation. The trans-membrane mass flux is controlled by the boundary layer heat transfer of both fluid channels. The estimation of heat transfer coefficients is critical to the analysis and design of MD modules. This paper presents the results of a comprehensive 3-D computational fluid dynamics (CFD) simulation which covers the entire length of the module and takes into account the trans-membrane heat and mass transfer. The model was verified with experimental data in the literature. The contour maps show that spacers create high velocity regions in the vicinity of the membrane. The trans-membrane heat and mass fluxes both show fluctuating patterns corresponding to the repetitive structure of the spaces and the fluxes are much higher than that of the modules using empty channels. The heat transfer coefficient enhancement factors obtained from CFD simulation are significantly higher than the predictions from literature correlations. The model can serve as an effective tool for developing correlations of heat transfer coefficients and optimal design of spacer-filled MD modules.