CaCO3 whiskers, as a micron-level inorganic fiber material, can enhance and toughen composite materials. In order to study the technical feasibility of CaCO3 whisker-modified asphalt, two types of silane coupling agent (SCA), KH-550 and KH-570, were applied to treat the surface of CaCO3 whiskers, and the treatment effects of the original and treated whiskers were characterized by scanning electron microscopy (SEM), energy-dispersive spectrometer (EDS) and contact angle test. Meanwhile, models of CaCO3 whiskers, SCA, and asphalt molecules were established by Material Studio (MS, 2020 version) software, and the adhesion mechanism between the CaCO3 whiskers-and-asphalt interface was predicted. The results of microscopic characterization experiments indicate that the surface of the whiskers treated with SCA became rougher. Compared with the original whiskers, the contact angle between the treated whisker surface and water increased from 50° to 92.2° and 103.4°, and the surface of whiskers changed from hydrophilic to hydrophobic. The results of molecular dynamics simulation analysis show that the adhesion performance between the CaCO3 whisker surface and asphalt increased from 100.1 mJ/m2 to 112.5 mJ/m2 and 126.6 mJ/m2 after modification with SCA, and the increase in adhesion energy of KH550 is greater than that of KH570. The above research results indicate that the micro-characterization results were consistent with the molecular dynamics simulation results; that is, after treatment with SCA, the adhesion energy between the whiskers and asphalt was increased to varying degrees. The research method in this article combines micro-characterization with molecular dynamics simulation, which has a certain degree of innovation.