The high-pressure polyethylene process uses cyclone separators to separate ethylene gas, polyethylene, and its oligomers. The oligomers larger than 10 microns that cannot be separated must be filtered through a filter to prevent them from entering the compressor and affecting its normal operation. When the separation efficiency of the cyclone separator is low, the filter must be cleaned more frequently, which will reduce production efficiency. Research shows that improving the separation efficiency of the separator is beneficial for the separation of small-particle oligomers and reduces the frequency of filter cleaning. For this reason, Computational Fluid Dynamics simulations were performed for 27 sets of cyclone separators to determine the effects of eight structural factors (cylinder diameter, cylinder height, cone diameter, cone height, guide vane height, guide vane angle, exhaust pipe extension length, and umbrella structure height) on separation efficiency and pressure drop. The equations for separation efficiency and pressure drop using these eight factors and the equations based on energy-efficiency parameters were determined. The optimization analysis showed that separation efficiency can be improved by 98.7% under the premise that the pressure drop is only increased by 8.2%. By applying the improved structure to the high-pressure polyethylene process, separation efficiency is increased by 17.7%, which could effectively reduce the frequency of filter cleaning for this process, and thereby greatly improve production efficiency.