Recently, some novel screens were proposed based on the improved understanding of screening processes from particle-scale studies, one of which is the novel variable amplitude equal thickness vibration screen (VAETVS). This paper presents an investigation of using different aperture sizes to further optimize the VAETVS by the discrete element method (DEM). The screen was divided into three panels, and the aperture size of each panel was varied in the simulation. The particles' dynamics and spatial distribution were investigated to better understand the effects of varied amplitudes and aperture sizes on the screening efficiency. The results showed that the VAETVS can be effectively optimized by varied amplitude as well as varied aperture size for different screen panels. The amplitude variance is more effective for hard sieve particles and hindrance particles. It is also found that from the feed end to the discharge end, the difference in the distribution of particle mass between the coarse particles and the fine particles increases. Generally, such a difference can be increased with increasing aperture sizes. However, the effects of the apertures of the different panels were not the same. The simulated data were further analyzed by the Box-Behnken response surface method, which gave a mathematical model to predict the screening efficiency η with the varied apertures. From the model, the optimal aperture sizes are 7.5, 7.58, and 6.81 mm, yielding the maximum screening efficiency of 86.35%, and the optimal opening areas for the three panels are 35, 40, and 40%, respectively, yielding the maximum screening efficiency of 87.82%.