In a ship assembly process, a large number of compliant parts are involved. The ratio of the part thickness to the length or the width is typically 0.001–0.012. Fixture design is a critical task in the ship assembly process due to its impact on the deformation and dimensional variation of the compliant parts. In current practice, fixtures are typically uniformly distributed under the part to be assembled, which is non-optimal, and large dimensional gaps may occur during assembly. This paper proposed a methodology for the optimal design of the fixture layout in the ship assembly process by systematically integrating direct stiffness method and simulated annealing algorithm, which aims to minimize dimensional gaps along the assembly interface to further improve the quality and efficiency of seam welding. The case study shows that the proposed method significantly reduced the dimensional gaps of the compliant curved panel parts in a ship assembly process.