Polytetrafluoroethylene (PTFE) plays an important role in semiconductor manufacturing. It is an important processing material for the key sealing components in the field of immersion lithography. The lack of research related to the mechanical processing of PTFE leads to many challenges in producing complex parts. This paper conducted a drilling experiment on PTFE. The effect of cutting parameters on the drilling performance was investigated. Thrust, torque, surface roughness, and drilling temperature were used to evaluate the influence of cutting parameters on drilling performance. In addition, the empirical mathematical models of thrust and torque were developed using analysis of variance (ANOVA). The results indicated that the spindle speed had the most important effect on the thrust and the feed rate had the most significant effect on the torque. The lowest values of thrust and torque were, respectively, 22.64 N and 0.12 Nm, achieved in the case of spindle speed of 5000 rev/min, and feed rate of 50 mm/min. The surface quality is also best at this cutting parameter. Studies have shown that higher spindle speeds with lower feed rates are ideal parameters for improving the drilling performance and machining quality of PTFE. In addition, it was found that the temperature differences due to different drilling depths were related to chip accumulation. Surface roughness inconsistencies at various locations in the inner wall of the hole were influenced by chip adhesion during machining. This paper provides a suggestion for optimizing cutting parameters and hole quality.