This study aims to develop a simulation-based research to evaluate the influence of primary operational conditions on the efficiency of compression molding in processing thermoplastic parts in a mold design with no air venting. Moldflow Insight has been used to simulate the compression molding process to assess the quality of a range of semi-crystalline and amorphous thermoplastic products, to study the performance efficiency of the said mold. Simulation results were obtained by varying the mold surface temperature, melt temperature, charge geometry and mesh element size during processing thermoplastics like polypropylene, polyethylene, polystyrene, and polycarbonate. The findings showcased air entrapment at the corners of the mold cavity, which lowered the process efficiency when the mold operated with no venting under varied processing conditions. Simulation results indicated a need to introduce air vents on the mold’s parting line. The findings revealed that the compression cycle time and waste generation could be diminished when air vents were included in the mold design and optimal operating conditions were used. Hence, a compression molding mold design incorporating air vents in areas of high air entrapment was developed.