Nano-ZnO has a large specific surface area, small particle size, and strong polarity and can be used as an additive to modify the base asphalt. In this paper, the compatibility mechanism between nano-ZnO modifier and asphalt is analyzed. Solubility parameters, interaction energNano-ZnO and mean square displacement of nano-ZnO in matrix asphalt were calculated at different temperatures to study the compatibility of the nano-ZnO modifier and the matrix asphalt. The radial distribution functions and radii of gyration of the asphalt’s four components under the action of the nano-ZnO additive were calculated to investigate the effect of nano-ZnO on the molecular structure of the asphalt. The results show that the best compatibility between nano-ZnO and matrix asphalt is observed at 150 °C, especially when the nano-ZnO particle size was 6 Å. The particle sizes of nano-ZnO have little effect on the temperature at which the nano-ZnO-modified asphalt achieved its highest structural stability. Around 150 °C, the nano-ZnO-modified asphalt system with different particle sizes exhibit the highest stability and best compatibility. The addition of nano-ZnO improves the compactness of the asphalt structure and makes the asphalt more stable.