In order to solve the problems of large size and thickness, unreasonable distribution of steel bars, difficult lifting, low material utilization, and long design cycle in the structural design of the tablet press frame. This article uses Ansys finite element analysis software to conduct force analysis and topology optimization of the tablet press frame, lightweight design of components, and form a structural optimization design scheme. We compared the model data before and after optimization. The mass before optimization was 378.6 kg, and after optimization it was 236.2 kg, a decrease of 25.87% in mass. The maximum equivalent stress decreased from 26.292Mpa to 12.695Mpa, and the displacement deformation after optimization was 0.101 mm. While meeting the design requirements, the overall stiffness performance of the frame has been improved, the design is lightweight, and the design cost has been effectively reduced. It has been applied in practical engineering and can provide reference and guidance for related industries.