Abstract: To address the lightweight design requirements of missile-borne electronic equipment structural housings, this study proposes an integrated design methodology combining topology optimization and response surface optimization. A dynamic load model of the housing was established based on the shock response spectrum (SRS). Topology optimization using the variable density method was conducted with the objective of minimizing mass and constraints on structural stiffness, achieving a 28.1% mass reduction. To resolve stress concentration issues at mounting lugs after topology optimization, a Kriging surrogate model was constructed through Latin Hypercube Sampling (LHS) experimental design, and key parameters—including lug wall thickness, height, and fillet radius—were optimized using a multi-objective genetic algorithm (MOGA). The final optimized design reduced the housing mass by 21.1% compared to the initial structure, decreased the maximum von Mises stress by 0.38% (from 171.45 MPa to 170.79 MPa), and satisfied the engineering safety factor requirement of ≥1.5. This methodology provides a high-precision and efficient solution for lightweight design of missile-borne equipment under shock loading conditions.