Motivated by the need to enhance the kerf quality during cutting of Poly(methyl methacrylate) (PMMA) sheets using pulsed CO2 laser beam, this study presents an experimental investigation and optimization of laser cutting parameters including cutting speed, assisted gas pressure, laser beam power, and sheet thickness. The kerf quality characteristics including the top kerf width, bottom kerf width, and kerf taper have been considered as the process responses and have been measured using polarized light microscope. The experiments were designed and planned using Taguchi L18 orthogonal array with a mixed design. The effects of different cutting parameters on the kerf characteristics have been statistically analyzed using analysis of variance technique (ANOVA). The obtained results revealed that any increase in cutting parameters will result in increasing the top and the bottom kerf widths, while increasing cutting speed or laser power results in increasing the kerf taper. Second order regression models have been developed to model different kerf characteristics as functions of the process parameters. Genetic algorithm (GA) has been used to select the optimal cutting parameters using the developed regression model as an objective function to minimize the kerf taper. A considerable improvement in kerf quality has been achieved and the obtained results have been verified using confirmation experiments. The application of the proposed approach is capable to reduce the kerf taper from 1.92° to 0.02° while maintaining the minimum kerf width at a reasonable value (less than 0.5 mm).