Methanol steam reforming (MSR) is a promising method for hydrogen supplying as a critical step in hydrogen fuel cell commercialization in mobile applications. Modelling and understanding of the reactor behavior is an attractive research field to develop an efficient reformer. Three-layer feed-forward artificial neural network (ANN) and Box-Behnken design (BBD) were used to modelling of MSR process using the Cu-SiO2 aerogel catalyst. Furthermore, impacts of the basic operational variables and their mutual interactions were studied. The results showed that the most affecting parameters were the reaction temperature (56%) and its quadratic term (20.5%). In addition, it was also found that the interaction between temperature and Steam/Methanol ratio is important on the MSR performance. These models precisely predict MSR performance and have great agreement with experimental results. However, on the basis of statistical criteria the ANN technique showed the greater modelling ability as compared with statistical BBD approach.