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The frontal impact is the most common in automotive collision accidents, and bending the sub-frame can directly lead to severe passenger injury and property damage. This research analyzed the crashworthiness, design, mechanical integrity, and optimization of an automotive front sub-frame structure. From the original geometry, a new sub-frame with similar mass and mounting locations is designed. Loads were applied to the front side members of the sub-frame to simulate a common frontal and partial frontal crash. A sub-frame with enhanced structural efficiency was designed using topology optimization. This improvement may preserve the lifespan of the sub-frame, reinforce the protection of passengers and the engine, and improve crashworthiness. Topology optimization is a numerical analysis technique that allows engineers to distribute materials optimally for a specific cost function. Iterative update of design variables typically relies on sensitivity information from performance analysis in each step. A simple parametric study on material candidates and design constraints was executed to evaluate various design options. Sub-frames with optimized geometries were mechanically tested against two different simplified loads mimicking frontal crashes. The dynamic behaviors were also analyzed and compared to the original design for validation.