Understanding the impact of configuration selection of industrial-scale membrane distillation (MD) is critical for a productive and energy-efficient operation of this emerging process for desalination. However, it is rarely considered even as new high flux membranes and wider applications are developed. In this context, three open source simulators were developed on the Matlab GUI platform for the performance prediction of industrial-size direct contact membrane distillation (DCMD), submerged vacuum membrane distillation (S-VMD), and cross flow vacuum membrane distillation (X-VMD). Using laboratory-scale experimental results as simulation inputs, the developed simulators were able to predict large-scale MD performance. Furthermore, design considerations on appropriate module scale-up for all three configurations were demonstrated. More importantly, the configuration that shows the optimal mass and heat transfer behaviour was revealed through the performance comparisons across different full-size MD configurations. In addition, these simulators are open-source allowing researchers to use these tools for the development of specific scale-up strategies of their own MD membranes - a critical step towards commercialisation.