To solve the disadvantages of the low protection grade, high weight, and high cost of the existing locomotive power battery system, this study optimizes the existing scheme and introduces the design concept of two-stage protection. The purpose of the research is to improve the protection level of the battery pack to IP68, to optimize the sheet metal power battery box structure into a more lightweight frame structure, to simplify the cooling mode of the battery pack for natural air cooling, and to improve the battery protection level and maintain the heat exchange capability. In the course of the study, a design scheme with a two-stage protection function is proposed. The numerical model analyzes the self-load, transverse load, longitudinal load, mode, and fatigue, and optimizes the layout of the power tank cell. The optimized box model was physically tested and economically compared. The results show that: (1) The maximum load stress is 128.4 MPa, which is lower than 235 MPa, the ultimate stress of the box material, and the fatigue factor of the frame box structure is 3.75, which is higher than 1.0, and it is not prone to fatigue damage. (2) Under the low-temperature heating condition, the overall temperature rise of the battery pack is 4.3 °C, which is greater than 2.3 °C under the air conditioning heat dissipation scheme. Under the high-temperature charging condition, the overall temperature rise of the battery pack is 2.0 °C, and the temperature value is the same as the temperature rise under the air conditioning cooling scheme. Under the high-temperature discharge condition, the overall temperature rise of the battery pack is 3.0 °C, and the temperature value is greater than 2.1 °C under the air conditioning heat dissipation scheme. At the same time, the temperature rise under the three working conditions is less than the 15 °C stipulated in the JS175-201805 standard. The simulation results show that the natural airflow and two-stage protection structure can provide a good temperature environment for the power battery to work. (3) The optimized box prototype can effectively maintain the structural integrity of the battery cell in the box in extreme test cases, reducing the probability of battery fire caused by battery cell deformation. (4) The power battery adopts a two-stage protection design under the battery power level, which can simultaneously achieve battery protection and prevent thermal runaway, while reducing costs. The research results provide a new concept for the design of a locomotive power battery system. (5) The weight of the optimized scheme is 2020 kg, and the original scheme is 2470 kg; thus, the reduction in weight is 450 kg. Meanwhile, the volume of the optimized scheme is 1.49 m3, and the original scheme is 1.93 m3; thus, the reduction in volume is 0.44 m3.