The configuration of trimaran is complex, and the side hull layout is of a great influence on its resistance performance. Based on the Computational Fluid Dynamics (CFD) theory, an automatic optimization method of side hull layout is constructed with the SHIPMDO-WUT software platform. Taken a high-speed trimaran ship for example, the optimization of side hull layout is performed. The results show that, under four different Froude numbers, the wave making resistances of optimized ship decrease compared with the parent ship, and the total resistances decrease correspondingly. The side hull layout scheme with the minimum total resistance under four different Froude numbers is obtained, which shows the feasibility and effectiveness of the method. The research content can provide reference for the trimaran resistance reduction optimization design.