Isocyanate esters are widely recognized for their superior curing capabilities. Leveraging this attribute, the current research formulated a modified cold-mixed asphalt blend using 4,4'-methylene diphenyl diisocyanate (MDI). Tests and analyses of the MDI-modified asphalt with varying inclusion percentages of MDI revealed that a mixture containing 15% rock asphalt and 15% MDI-modified asphalt exhibited a more balanced, comprehensive performance. We also conducted an examination of the role and properties of MDI in asphalt modification using molecular dynamics simulations. The cold-curing properties of MDI-modified asphalt as compared to petroleum asphalt were evaluated based on its density, free volume analysis, cohesive energy density, and glass transition temperature. Implementing the LB-13 gradation-a cold-mixed asphalt gradation with a nominal particle size of 13.2 mm recommended by Chinese specifications-we prepared MDI-modified cold-mixed asphalt and carried out analyses of its mechanical characteristics, high-temperature performance, and water damage resistance. The results demonstrated that MDI-modified asphalt showcases excellent ductility, flexibility, and aging resistance, surpassing the performance of petroleum asphalt. The stability, high-temperature rutting, and water damage resistance of the MDI-modified cold-mixed asphalt exceeded the requirements for hot-mixed asphalt. This research provides theoretical and experimental support for isocyanate ester applications in asphalt engineering, presenting significant value for practical engineering applications.