Polyurethane-modified asphalt demonstrated the enhanced durability and skid resistance, while remaining the drawback in the compatibility between the polyurethane modifier and asphalt binder in practical use. Herein, a molecular-dynamics-simulations based compatibility evaluation method is proposed for the polyurethane modifier and asphalt binder, thereby achieving the cost-effective and efficient components optimization. Twelve components asphalt molecular model was built in Molecular Dynamics to investigate the interaction of asphalt binder to the polypropylene glycol, toluene diisocyanate, and diphenylmethane diisocyanate, respectively. The molecular model of polyurethane modified asphalt binder was verified by the similar loss modulus temperature from the simulation and temperature scanning tests. The simulation outcomes indicate significant variations in the compatibility of different polyurethanes with asphalt, in which diphenylmethane diisocyanate-type polyurethane exhibits the superior compatibility. The compatibility of various polyurethane concentrations in asphalt shows considerable disparity, suggesting that the compatibility index can serve as a criterion for determining the optimal dosage of the modifier. Temperature also exerts an influence on the compatibility of polyurethane modified asphalt binder. Simulation results indicates that 130 °C potentially may be the optimal temperature for its preparation, which is corroborated by the microscopic characterization. This study provides a fundamental framework for the molecular dynamics simulation-based components optimization of polyurethane-modified asphalt, thereby inspiring the targeted design of asphalt materials.