Long-distance buried pipelines are one of the most common and economical transportation methods for oil and gas, but the fault movement will pose a threat to the safety of pipelines. The main challenge of pipeline under strike-slip faults is to improve the ability of resistance to fault dislocation, and the main aim of the study is how to improve the critical fault displacement of pipelines with the help of polyurethane isolation layer. Three-dimensional finite element models were proposed for mechanical analysis of X80 buried steel pipe with polyurethane isolation layer under strike-slip fault. The influence of factors on the mechanical properties of pipelines were studied, such as thickness of isolation layer, internal pressure, fault displacement, diameter-thickness ratio, and the angle of pipe and fault line. The simulation results indicate that with the increase of the thickness of the isolation layer, the development of the maximum tensile and compressive strain of the pipeline is significantly reduced for the same fault displacement, resulting in a significant increase in the critical fault displacement corresponding to the three failure modes of the pipeline. As the ratio of diameter to thickness and internal pressure decrease, the critical displacements decrease. When designing and planning the pipeline, pipeline is recommended with the seismic isolation layer, large wall thickness, and the crossing-angle at 70 deg∼80 deg. The research provided a reference for judgment of earthquake resistance, failure analysis, and safety design of pipelines with polyurethane isolation layer crossing strike-slip faults.