Crane frame is one of the core components of the crane. Important performance indexes for the design of a frame include stiffness, manufacturability, and durability. Simultaneously, lightweight of the frame is also critical for decreasing the consumption of manufacturing and transportation. Crane is a complicated multibody structure, and therefore, using the traditional method to analyze will consume large amounts of computing time, and the accuracy cannot be expected. In order to solve these problems, a novel and effective method, super-element global modal parameterization, is employed in this article. The advantages of using this approach are that the complex models can be reduced, while the important effects are still taken into account. The design procedure consists of three steps: first, the finite element model is used to analyze the original frame. Then, the stiffness and von Mises stress obtained from the analysis are treated as the design constraints in the next topology and thickness optimization. Finally, a validation of the optimum design for durability is performed, and the results show that all the performances satisfy the requirements. The frame structure has a 15.12% reduction in total mass, while the performance is improved compared to the original.