To secure the precision forming capability of a press while reducing its production and transport costs, the development of stiff and lightweight frame is important. In this study, the topology and multi-objective structural optimization problem of a frame structure was introduced with an effort to develop highly stiff and lightweight frame for a mechanical press with 300 ton capacity. First, a design space model was constructed to derive a new frame structure different from the existing one for topology optimization. Using the design of experiments and the structural analysis model of the frame structure improved based on the topology optimization result, the multi-objective optimization problem was established with loop stiffness and mass of frame as objectives and the steel plate thickness as design variable. The review on Pareto optimum solutions of the multi-objective optimization problem revealed the fact that this optimization method could significantly contribute to the high stiffness and lightweight frame structure for a mechanical press.