To control the global surface variations is highly important for improvement of surface properties and it relies on robust process design of process parameters and fixture layout. However, due to the changes of milling conditions, the controlling of surface variations based on discrete sampling of interest points is hard to meet the global optimal in entire milling surface. To address this issue, this paper attempts to provide a methodology to optimize process parameters and fixture layout iteratively towards minimum the machined global surface variations based on the finite element model updating (FEMU) method and genetic algorithm (GA). The global surface variations are determined by a coupled numerical model via FEMU, which enable iterative finite element simulations to decouple the force-deformation coupling at each instant milling moment and also renew the updating of changing milling conditions along with the changing of milling locations during the whole face milling process. In optimization process, the milling parameters and fixture layout are updated in finite element model via FEMU method and optimally selected via GA based on the global surface variations prediction. Based on the proposed method, the continuous milling parameters and discrete fixture layout can be optimized with minimum global surface variations simultaneously. It provides a comprehensive methodology to control the global surface variations in face milling of variable stiffness structure for its industry implementation.