Wire mesh demisters, as high-efficiency separation equipment, play a critical role in determining the efficiency and energy consumption of industrial separation processes. In order to enhance the overall performance of wire mesh demisters, this study investigates the effects of wire diameter, mesh diameter and the number of layers on separation efficiency and pressure drop, and conducts an optimization design based on the Response Surface Methodology. On the premise of ensuring data quality, the Box-Behnken design is used to improve the efficiency by selecting the minimum number of design points. A three-dimensional simplified model of the wire mesh demister was developed, and numerical simulations were performed to generate multiple datasets for various combinations of wire diameter, mesh diameter and the number of layers. Based on these data, a quadratic regression model was established to evaluate the influence of wire diameter, mesh diameter and the number of layers on separation efficiency and pressure drop. The optimal structural parameters were determined using response surface optimization methods. The results indicate that the number of layers significantly affect the separation efficiency and pressure drop of wire mesh demisters. The optimized design achieves improved separation efficiency while significantly reducing pressure drop. The proposed optimization method provides reliable data support and theoretical guidance for enhancing the performance of wire mesh demisters, laying an important foundation for future design and applications.