Moisture diffusion is one of the mechanisms by which water can reach the microstructure of asphalt mixtures and negatively affect their performance. In this work, a finite element model and computational simulations were used to study the response of asphalt pavement layers subjected to the coupled effects of moisture diffusion and mechanical loading. The model considered that the evolution of water-related diffusion processes in these materials is influenced by the microstructure of the mixture, particularly by the air void (AV) phase. Thus, a stochastic technique was used to incorporate the heterogeneity of the AV structure in compacted asphalt layers, which also permitted to account for the variability of the physical and mechanical properties that result from the heterogeneous void structure. The results demonstrate that moisture diffusion has a significant influence on the macromechanical response of asphalt pavement layers, especially during the initial months of service. In addition, the results clearly demonstrate that including the heterogeneity of material properties is valuable to quantify the uncertainty associated with these coupled processes.