The design of low dielectric loss epoxy resin (EP) systems plays an important role in the insulation optimization of medium-frequency transformers (MFTs). Due to the diversity of EP and curing agents, the traditional design method inspired by dielectric-loss measurements cannot reduce the low dielectric-losses of EP system designs from plentiful candidate EP systems. In this study, molecular dynamic (MD) computations were introduced to drive the design of a low dielectric-loss EP system for MFTs. By analyzing the relationship between dielectric loss and molecular motion of EP systems, two MD results were selected as descriptors for indicating the dielectric loss of EP systems, including mean square displacement and α-transition temperature. Eventually, a low dielectric-loss EP system blending EP, methyl tetrahydrophthalic anhydride, and dodecenyl succinic anhydride was effectively designed according to the descriptors. The rationality of the computation-driven design was verified by broadband dielectric spectroscopy measurements and finite element method. Compared with previous EP systems, MFT insulated with the designed EP system had not only a 40% lower dielectric loss (9.79 W) but a higher overload capacity. This study provides an effective method for the design of low dielectric-loss EP systems.