Membrane distillation (MD) is a process to desalinate sea water. Pilot plants are operated aiming at increasing the modules’ efficiency for large-scale applications. In air-gap membrane distillation (AGMD) the state-of-the-art modeling of mass and heat transfer is one-dimensional, combining evaporation and diffusion through the membrane and the condenser channel in one correlation. In this work, a numerical model is developed which computes AGMD modules in three dimensions. For evaporation and condensation, energy conservation equations at the interfaces are solved. Simulation results are compared to experimental data and a good agreement is found. The model is then employed to compare numerically two air-gap MD module configurations and evaluate their performance at different feed inlet temperatures, velocities and air-gap thicknesses. In the upside configuration, the hot feed flows above the membrane, while in the downside configuration it flows below the air-gap and membrane. In the latter, the feed solution is not in contact with the membrane but separated by the air-gap which is expected to improve the fouling resistance of the membrane. The three-dimensional computational fluid dynamic computation allows the visualization of the velocity profile in the air-gap due to buoyancy in the downside configuration.