Minimum quantity lubrication (MQL) is a promising solution as an alternative to conventional flood cooling and dry machining. This study investigates the enhancement of drilling performance through the application of hybrid (Al2O3 + CuO) and unitary (Al2O3) nanofluids in the MQL system, focusing on thrust force, torque, friction coefficient, and the final surface quality. A full factorial design of experiments was employed to evaluate the effects of lubrication type, nozzle configuration (number, geometry, and outlet diameter), and their interactions under identical conditions. Results demonstrated that hybrid nanofluids outperformed unitary nanofluids, achieving reductions of 51% in thrust force, 56% in torque, and 42% in friction coefficient compared to dry machining when using four rectangular nozzles with a 1.5 mm outlet. Increasing the number of nozzles from one to four enhanced lubricant distribution, reducing thrust force, torque, and friction by 22%, 23%, and 38%, respectively. Rectangular nozzles with a 1.5 mm outlet proved effective due to superior spray coverage, while ANOVA identified number of nozzles and nozzle geometry as the most influential parameters. Surface quality improvements, including reduced burrs and cracks, were observed with hybrid nanofluids, enhancing precision and fatigue life. Multi-criteria optimization via TOPSIS confirmed the hybrid nanofluid MQL system with four rectangular nozzles (1.5 mm) as the most effective configuration. These findings underscore the potential of advanced MQL strategies to improve machining efficiency, tool life, and surface integrity in green manufacturing.