In order to improve the self-sufficiency rate of key mineral resources in China, it is necessary to develop and research deep-sea mining vehicles to improve the mining capacity of seabed mineral resources. The deep-sea mining vehicle is a heavy-duty underwater robot, and its main frame structure, as a critical component, must be designed to be lightweight to improve payload capacity and mining efficiency. This paper first conducted static analysis for the initial main frame structure. Finite element analysis results indicate that the initial structure fails to meet the strength requirements for lifting and recovery operations. The power index penalty factor was introduced into the topology optimization, which was based on the variable density method. The topology optimization objective was set to minimize structural compliance, with the maximum element stress and volume fraction used as constraints. The optimization process finally obtained the optimal material distribution. According to the results of topology optimization and space requirements of the installed equipment on the deep-sea mining vehicle, the new frame structure of the mining vehicle was re-established in the secondary modelling. According to the results of the analysis, the weight of the frame structure was reduced by 2.9%, and at the same time, the maximum stress was reduced by 57.2%, the maximum displacement was reduced by 47.2%, and the first-order natural frequency was increased by 54%. The strength and stiffness of the frame structure were greatly improved.