The optimization of critical drilling parameters in Glass Fiber Reinforced Polymer (GFRP) nanocomposites was investigated, focusing on spindle speed, feed rate, drill diameter, stacking sequence, and nanofiller composition. Nanofillers such as MgO and TiO2, combined with tailored fiber layer arrangements, were employed to enhance hole quality. Nanocomposite laminates were fabricated using the vacuum bagging process. Key parameters, including feed rate (0.8, 0.9, and 1.0 mm/rev), spindle speed (500, 1000, and 1500 rpm), drill diameter (8, 9, and 10 mm), stacking sequences, and nanofiller compositions, were analyzed using the Taguchi L27 (35) orthogonal array and ANOVA. Results revealed that feed rate significantly impacts hole quality, while spindle speed plays a secondary role in determining hole quality. Optimal parameter combinations achieved superior drilled hole quality. The regression model and confirmation tests exhibited a strong correlation between experimental and predicted outcomes, validating the model’s accuracy in optimizing drilling performance.