This study proposed an effective method for optimizing laser drilling processing (LDP) by using grey relational analysis (GRA) for multiple performance requirements. First, we developed a system using a Quantel Brilliant Neodymium-doped Yttrium Aluminum Garnet (Nd: YAG) laser with a pulse width of 5–6 ns and F-theta lenses to deliver a focused laser beam with a diameter of 0.2 mm. The developed system was first employed to drill holes in a 3-mm-thick optical-grade acrylic polymethyl methacrylate (PMMA) plate on a safe window with a high optical density and a grade of OD 7+ @ 950~1085 nm. To avoid errors in the experimental data due to unstable power, a laser power (energy) meter was used to measure the energy stability of the Quantel Brilliant Pulse Laser. Given the stability of 5.6%, this is an effective method for LDP. Four control factors were investigated, including laser pulse energy, repetition rate, focusing position offset, and drilling time. Then, nine experiments were performed using the Taguchi method with orthogonal arrays in L9 (34). The experimental results with multiple quality characteristics were measured and used to optimize the control factors by using GRA with equal weighting of the four qualities (roundness, Hillock ratio, taper, and HAZ). The results show that A1B3C1D1 is the optimal combination of the control factors, and the maximal variation of 0.406 is obtained from the control factor B (focusing position offset) which has the greatest contribution to the drilling time. We then performed confirmation experiment and obtained a better result from the combination of the control factors, A1B3C1D1. GRA helps us determine the best laser drilling parameters to meet the desired multiple drilling qualities.