The influence of several process parameters like milling time, ball-to-beaker volume ratio, diameter of milling balls, and rotation frequency on the Knoevenagel condensation of vanillin and barbituric acid in planetary ball mills was investigated. These parameters determine the amount of energy provided for the reaction. Additionally, numerical simulations were carried out to describe the stress conditions in detail and to compute the drive power and energy transfer which cannot be measured directly. The mill and experimental parameters were modeled by the discrete element method with adequate coefficients of friction and restitution required to describe the powder behavior in the system. The coefficients were determined by correlation of experiments and simulations.