Abstract: To address the seismic safety of the main steam pipeline in nuclear power plants under large displacements induced by base isolation, this study identifies the key components—straight pipes, elbows, and spatial elbows—based on the deformation capacity ratio analysis of the optimized pipeline layout. A layout optimization strategy involving the introduction of elbows is proposed and analyzed in detail. A numerical analysis model is established and validated against experimental results. Parametric studies are further conducted to investigate the influence of diameter-to-thickness ratio, bending radius, and bending radius ratio of key components on deformation capacity and the Park–Ang damage index. The results show that under maximum cyclic displacement loading, reducing the diameter-to-thickness ratio of the straight pipe component from 35.6 to 16.2 increases the peak load by 111.7% and decreases the damage index by 15.2%. Increasing the bending radius of the elbow component from 2100 mm to 3000 mm results in an 11.8% increase in peak load and a 15.7% reduction in the damage index. These findings indicate that reducing the diameter-to-thickness ratio of straight pipes and increasing the bending radius of elbows significantly enhance the deformation capacity and reduce the damage level of the components. For spatial elbows, increasing the bending radius ratio from 0.7 to 1.33 leads to a 12.8% increase in peak load but also a 6.2% increase in the damage index, suggesting that although a larger bending radius ratio improves deformation capacity, it also makes the component more susceptible to damage. Based on the parametric analysis of key components, two pipeline layout optimization schemes are proposed. Time-history seismic analyses of the optimized main steam pipelines are performed, and the results show that the peak stresses of the two optimized schemes are reduced by 40.2% and 50.6%, respectively, compared to the original design. These findings demonstrate that the optimized pipeline configurations exhibit excellent seismic performance and can meet the large-displacement deformation requirements of base-isolated nuclear power plant design.