In this paper, a novel comprehensive permeation model for mixed matrix membranes (MMMs) is introduced. This model shows the importance of understanding and developing a more reliable model for the permeation behavior of MMMs containing porous filler nanoparticles. A new method is established to provide a more precise/large‐scale three‐dimensional MMMs geometry. The required number of spherical porous fillers in random/nonuniform positions in the polymer matrix is calculated. Interfacial equilibrium constant (K) at the polymer/filler interfaces was adjusted as the concentration ratio of the diffusing penetrants (C2 and C1) at the interface, respectively. In this case, the K values are changed by varying the intended gaseous concentration due to their permeation through the MMM. Hence, its effect on penetrants effective diffusion coefficient was examined. Then, the obtained results were evaluated with similar experimental data, which showed much consistency. Therefore, the accurate calculation method for MMMs permeability was governed for the entire range of the operating pressures in MMMs. The results showed that the permeability of MMMs increases with increasing filler particle size. On the other hand, variations that occur in the MMM permeability at various particle size were much more distinct at higher loadings. Moreover, some well‐known analytical permeation models were used to compare and validate the model's permeability results. It can be concluded that this model provides a method for more precise and realistic design of MMMs as well as to better construe the large number of related experimental data. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.