Rolling stock manufacturers are finding innovative structural solutions to improve the quality and reliability of railway vehicles components. Structural optimization processes represent an effective strategy for reducing manufacturing costs, resulting in geometries easier to design and produce. In this framework, the present paper proposes a new methodology to design a railway metro bogie frame, combining structural–topological optimization methods and sensitivity analysis. In addition, manufacturing constraints were included to make the component design suitable for production through sand-casting. A robust sensitivity analysis has highlighted the most critical load conditions acting on the bogie frame. Its effectiveness was verified by carrying out two different structural optimizations based on different loadings. Two equivalent designs were obtained. Computational times were positively reduced by about 57%. The maximum value of stress was reduced about 23%. This new methodology has shown encouraging results to streamline the design process of this complex mechanical system, allowing researchers to also include manufacturing requirements.