In the milling of large monolithic structural components for aircraft, 70-80% of the total cut volume is removed using high-speed roughing operations. In order to achieve the economic objective (i.e. optimal part quality in minimal machining time) of this process, it is necessary to determine the optimal cutting conditions while respecting the multiple constraints (functional and technological) imposed by the machine, the tool and the part geometry. This work presents a physical model called GA-MPO (genetic algorithm based milling parameter optimisation system) for the prediction of the optimal cutting parameters (namely, axial depth of cut (a(p)), radial immersion (a(e)), feed rate (f(t)) and spindle speed (n)) in the multi-tool milling of prismatic parts. By submitting a preliminary milling process plan (i.e. CL data file) generated by CAM (computer-aided manufacturing) software, the developed system provides an optimal combination of process parameters (for each machining feature), respecting the machine-tool-part functional/technological constraints. The obtained prediction accuracy and enhanced functional capabilities of the developed system demonstrate its improved performance over other models available in the literature.