Abstract: To investigate the progressive collapse resistance of unbonded post-tensioned precast concrete (UPPC) beam-column substructures under the condition of middle column failure, a high-fidelity finite element model was established using ABAQUS. The model was validated against existing experimental specimens, demonstrating a good accuracy in predicting load-displacement responses, failure modes, and stress development in prestressing tendons. A parametric study was conducted to systematically evaluate the effects of tendon layout, of initial prestress level, and of the ratio of prestressing tendon on the behavior of progressive collapse resistance. Research results indicate that a two-line tendon layout effectively enhances both the capacity of compressive arch action and ductility. While increasing the initial prestress level improves the resistance in the compressive arch stage, it leads to an earlier tendon fracture, thereby weakening the catenary action in the large deformation stage. Higher reinforcement ratios significantly increase the ultimate load-bearing capacity; however, excessive reinforcements are easy to aggravate the transformation of the structure to the failure mode of “strong beam and weak column”, which is unfavorable to the seismic resistance. Furthermore, a theoretical model based on the mechanical equilibrium and on the deformation compatibility was proposed to calculate the resistance contributions of both compressive arch and catenary mechanisms. The model proposed accurately predicts the structural resistance throughout the collapse process, showing a good agreement with experimental and numerical results.