Abstract: The development of ultra-high-speed maglev transportation systems relies on prefabricated low-vacuum pipelines, but during long-term operation, differential settlement of foundations causes pipeline deformation, which coupled with vacuum pressure easily leads to structural joint failure and sealing failure. In this study, a low-vacuum pipeline experimental platform was employed to conduct structural model tests, and numerical simulations were further used to analyze the mechanical behavior of prefabricated pipelines under the coupled effects of differential settlement and vacuum pressure. The results show that vacuum pressure causes circumferential compression and axial tensile deformation of the pipeline. When vertical displacement occurs at the joints, pipeline stress and deformation increase, and with increasing displacement, both circumferential and axial stresses exhibit alternating strong–weak patterns accompanied by internal force redistribution. When the vertical displacement of joints is 2 mm, the circumference of the pipeline remains under compression, while the axial direction experiences tensile stress at the crown and compressive stress at the invert. When the vertical displacement reaches 5 mm, the maximum axial tensile stress at the crown is 4.67 MPa, the maximum compressive stress at the invert is –5.46 MPa, and the circumferential stress distribution becomes non-uniform. These findings indicate that extreme differential settlement has a pronounced effect on the stress and deformation of pipeline structures, thereby placing higher demands on the structural design of prefabricated low-vacuum pipelines.