In order to counter the problems of cracks and large area fractures in the welding points of quick-replacement battery boxes for electric vehicles (which may lead to the concentration of stress), in this study, a fatigue analysis of the welding points, based on a load spectrum, was used to predict welding points’ fatigue and improve the structural life of quick-replacement battery boxes. Firstly, a model of the quick-replacement battery box was established in SolidWorks software; secondly, the welding points’ fatigue was analyzed using the Optistruct module of HyperMesh software, and the topology of the quick-replacement battery box was optimized according to the results of the analysis; finally, for testing purposes and to achieve a lighter weight and an improved structural life, the fatigue of the welding points of the optimized battery box was analyzed. The results of the analysis showed that the force of the quick-replacement battery box was primarily concentrated at the connection between the middle bottom plate and the partition. Additionally, retaining the number of welding points at the hanging ear was shown to be beneficial for maintaining stiffness during electric vehicle operation; however, the number of welding points at the partition connection could be appropriately reduced. Before optimization, the maximum fatigue damage values of the welding points were 2.763 × 10⁻⁶, 3.833 × 10⁻⁶, and 6.728 × 10⁻⁶, respectively, satisfying the criteria of fatigue damage to the welding points. After optimization, the fatigue damage values of the welding points in the quick-replacement battery box were significantly reduced to 4.431 × 10⁻⁸, 4.562 × 10⁻⁸, and 8.885 × 10⁻⁸, respectively, compared with their pre-optimized levels. Consequently, the stress concentration was alleviated effectively, thereby meeting the conditions for fatigue damage. These results have important theoretical and engineering significance for the design and optimization of quick-replacement battery boxes for electric vehicles.