Secondary flow limits the aerodynamic loading level of turbomachinery. Vortex generators (VGs) offer the potential to attenuate secondary flow when implemented at the endwall of the blade passage. Customary design usually relies on computational fluid dynamics (CFD); however, VG geometry modeling and mesh generation are challenging. This paper presents an efficient method for designing the optimal VG layout. In this approach, first, a mathematical model (BAYC) is introduced to replace the actual VGs; hence, simulation can be carried out without detailed VG gridding. Second, an optimization procedure with response surface methods is employed to determine the optimal VG layout. To illustrate the proposed method, compressor cascades with one and three VGs are used as the test cases. The results demonstrate that the optimal VG layout may effectively weaken the secondary flow and can decrease the aerodynamic loss by 15–25% in almost all incidence angle ranges, particularly at positive incidence angles. Flow mechanism analysis indicates that VGs can enhance the boundary layer kinetic energy, thereby elevating the capability to withstand adverse pressure gradients.

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