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In the present study, laser milling tests were carried out on aluminium oxide (Al₂O₃) plate, 3 mm in thickness, using a Q-Switched 30 W Yb:YAG fiber laser. A systematic approach based on Design of Experiment (DoE) has been successfully adopted with the aim to detect which and how the process parameters affect the laser beam–material interaction, and to explain the effect of the process parameters on the material removal rate and surface quality. The examined process parameters were the laser beam scan speed, the pulse frequency, the total energy released for surface unit, the distance between two consecutive scan lines and the scanning strategy. A full factorial design and ANalysis Of VAriance (ANOVA) were applied for the results analysis. Finally, the various effects of the process parameters on the material removal rate and surface roughness have been analysed and discussed.