The application of Computer-Aided Engineering (CAE) tools in mechanical design has consistently increased over the last decades. The benefits introduced by virtual models in terms of time and cost reductions are the main drivers for their exploitation in industry as well as for research purposes in academia. In this regard, Computational Fluid Dynamics (CFD) can be exploited to study lubrication and efficiency of gears. However, the mesh handling complexities deriving from the boundary motion is still a concern for its application to multi-stage gearboxes. In this work, an innovative multi domain partitioning method for the simulation of a two-stage industrial speed reducer is presented. The implemented solution foresees the combination of two remeshing strategies, namely GRA (Global Remeshing Approach) and GRAMC (GRA with Mesh Clustering), and resulted in a computationally effective performance. The results were compared with experimental data obtained with measurements on the real system, providing a good agreement in the power losses prediction. Considering the complexity of obtaining such results experimentally, the proposed numerical algorithm can offer substantial benefits for an estimation of the transmissions’ efficiency in various operating conditions. The numerical model was built in the open-source environment OpenFOAM®.