The aim of this work was the development and optimization of enzymatic monolithic membranes with high catalytic activity for the degradation of xylan into xylooligosaccharides. The chemometric tool design of experiments has been utilized here for the first time for the optimization of the enzymatic activity of the monolithic membranes based on their constituents. The effect of three process variables, including the amount of various monomer contents and the porogenic solvents ratio, has been studied on the enzymatic activity of the resulted membranes. The experimental design chosen was a central face centred with six central points in order to obtain an orthogonal model, with the precision of the results being independent of the range of values considered for each parameter. The software Modde(c) 6.0 from Umetrics(c) was used to build and analyze the results of the experimental design using partial least squares regression. The optimization of the suggested model provided the best membrane composition to achieve maximum enzymatic activity, which can be related to the amount of enzyme immobilized on the monolithic membrane. The predictive capacity of the model was evaluated performing additional experiments.