We developed the compact battery pack with structural safety and high cooling performance based on numerical simulation for hybrid electric vehicle (HEV) applications. The most important requirement in HEV battery pack is high specific power (kW/kg), which makes lightweight design of battery pack essential. By applying optimization methodology combined with structural finite element analysis, robust and lightweight module frame, which binds dozens of batteries together, was designed to minimize the deformation of batteries in case of swelling or explosion. Efficient cooling system was also achieved through the Pugh decision matrix with computational fluid dynamic analysis, to have a uniform temperature distribution and a minimized pressure drop within the pack under normal charging/discharging conditions. By employing module frame and cooling system based on numerical simulation, the compact design of lithium-ion battery pack was obtained successfully to have structural safety and cooling performance. Experiments were implemented to further validate numerical simulation of thus obtained optimal battery pack design for HEV, and they were found to be in good agreement.