This study evaluates CNC milling parameters (spindle speed, depth of cut, and feed rate) on medical-grade PMMA. A single objective analysis conducted showed that the optimal material removal rate (MRR) occurs at a spindle speed of 1250 rpm, a depth of cut of 1.2 mm, and a feed rate of 350 mm/min. The ANOVA showed that feed rate is the most significant factor towards the MRR, and spindle speed (11.83%) is the least contributing. The optimal surface roughness (Ra) occurred at spindle speed of 500 rpm, depth of cut of 1.2 mm, and feed rate of 200 mm/min. The milling factors were insignificant. A regression analysis for prediction was also conducted. Further, a multi-objective optimization was conducted using the Grey Relational Analysis. It showed that the best trade-off between the MRR and the Ra could be obtained from a combination of 1250 rpm (spindle speed), 1.2 mm (depth of cut), and 350 mm/min (feed rate). The depth of cut was the largest contributor towards the grey relational grade (54.48%), followed by the feed rate (10.36%), and finally, the spindle speed (4.28%).