Ethylene oxide-tetrahydrofuran copolyether (P(E-co-T)) crosslinked with isocyanate Desmodur (N100) is widely used as the binder system in solid energetic propellant. The effect of its cross-linking degree on the physical properties is important for the evaluation of the propellant binders. In this work, an efficient method was presented for simulating the cross-linking process, predicting the microscopic behaviors and macroperformances of cross-linked P(E-co-T)-N100 binder systems. During the simulation of cross-linking network forming, the initial physical mixture model of P(E-co-T)-/N100 was firstly constructed and optimized through molecular dynamics. Then the possible cross-linking topology was generated by means of the identification of the reactive site pairs. In this way, the P(E-co-T)-N100 cross-linking pathway was realized by alternate structure optimization and junction reaction. The cross-linking intermediate models were analyzed, and the density and mechanical property profiles have revealed the increasing tendency with cross-linking progressing, which is corresponding to the experimental results. Moreover, volume-temperature behaviors of P(E-co-T) and cross-linked P(E-co-T)-N100 systems were simulated to study the cold resistance characterized by glass transition temperature. The mean-squared displacements and free volume data have verified that the cross-linking structure of P(E-co-T-)N100 restricts the molecular mobility, which is helpful to explain the higher glass transition temperature and stronger mechanical properties.