Spiral guide vanes are often used to improve the collection efficiency of cyclone separators, but they are closely related to the parameter variables of the guide vanes. To further improve the performance of the equipment, the separator and spiral guide vanes need to be optimized. In this study, the performance characteristics of the flat-roof (FR) and spiral-roof (SR) separators were compared, and then the multiobjective optimization of the guide vanes was carried out. The design relationship between the parameters of the spiral guide vanes (pitch, number of turns, and side wall clearance) was analyzed and the optimal values were determined. computational fluid dynamics (CFD) and response surface modeling (RSM) were used to obtain precise output responses, while precise fitness functions were constructed between design variables and objectives (efficiency and pressure drop). Finally, the optimal structure design was carried out through a genetic algorithm (GA). The results show that, under the same conditions, the SR separator configured with guide vanes can reduce the pressure drop by 7.9% while ensuring the same collection efficiency. At the same time, compared with the FR separator, the optimal structure selected reduces the cutting particle size by 22.9%. This article gives the optimal performance design solution, which can select appropriate structural parameters according to the specific requirements of efficiency and pressure drop. It can provide an effective reference for the subsequent design and application of spiral vanes.