The development of eco-friendly desalination and water reuse is key to secure water for future generations. The hybridization of emerging membrane technologies such as forward osmosis (FO) and membrane distillation (MD) stand among alternatives that proved sustainable in treating various feeds. As such, in-series integration of MD and FO enabled the simultaneous treatment of challenging streams, with MD producing fresh water while increasing the draw solution concentration before FO treatment. It is within this context that numerical modeling plays a key role by accelerating hybrids process design and scale-up, shedding light on viable directions and shortening development time. This work presents an advanced 3D multiscale modeling approach that integrates FO and MD heat and mass transfer membrane scale calculations to equipment scale computational fluid dynamics, executed on high performance computers. A methodology based on laboratory scale FO-MD integrated module experiments and runtime optimization is proposed for model calibration and process scale-up. The parallelization of the numerical model is shown to be key to efficient integrated modules development, enabling full 3D analysis on fine meshes and the solution of intricately coupled physical phenomena, which leads to a straightforward process scale-up evaluation.