Impaired pulmonary gas exchange in respiratory diseases is caused by a large extent by the physiological mechanism of ventilation–perfusion (V/Q) mismatch. This study is aimed at developing a mathematical modelling framework to quantify regional ventilation, pulmonary perfusion and oxygen transport by coupled nonlinear differential equations. A novel model called Adaptive Ventilation–Perfusion Coupling Model (AVPCM) is proposed which is numerically solved using the Finite Difference Method (FDM) with an implicit Crank–Nicolson time integration scheme, which guarantees stability and accuracy of the calculations. The accuracy at which the simulation results achieved prediction of V/Q mismatch (92.8%), estimation of oxygen saturation (91.3%), prediction of the regional ventilation (89.7%) and the mean prediction error (13.5%) were lower than that of a conventional compartmental model. The framework is physiologically consistent, numerically stable and efficient in terms of computational resources, thus supporting the mathematical modeling of respiratory diseases and the assessment of pulmonary function in patients.