Hydrate form spontaneously in submarine oil/gas pipelines. The large-scale aggregation of hydrate cause pipeline blockage and threatens safe oil/gas production. The use of anti-agglomerant agents (AAs) is a cost-effective method to prevent hydrates from clogging pipeline. However, conventional AAs such as Span 80 are not applicable in oil/gas pipelines rich in asphalt, because asphalt is easy to occupy the binding sites on the water droplet surface. Through molecular simulation, it is found that cyclodextrin (CD) shows excellent anti-agglomerant characteristics in oil–water system containing asphalt by forming stable hydrogen bonds with water molecules. CD and asphalt interact through electrostatic and dispersive interaction to form stable W/O supramolecular surfactant. Compared with Span 80, the initial contact time between water droplets and hydrate is delayed by 5 times (from 22.1 ns to 113.9 ns) after adding CD molecules. The contact angle of water droplets on the hydrate surface also increased from 48.4 ± 2.4° to 64.4 ± 2.2°. CD-asphalt interaction prevents water droplets from spreading on the hydrate surface by maintaining the stability of emulsion. The unique properties of CD provide a molecular basis for the development of more green and efficient AAs. Subsequent research will be carried out around the compounding of CD and other AAs, and it is expected to play a better anti-aggregation effect.