The effect of asphalt aging on the moisture resistance of hot-mix asphalt (HMA) is still controversial and scarcely investigated. Our study is aimed at revealing the change to moisture susceptibility of HMA upon aging based on the fundamental chemistry of asphalt and laboratory performance tests. It was found that both short-term (rolling thin film oven (RTFO)) and long-term (pressure aging vessel (PAV)) aging significantly impaired the properties of asphalt and increased the debonding potential per unit contact area at the asphalt−aggregate interface. The energy ratios (ERs) of different asphalt−aggregate combinations decreased 11.60−59.68% upon aging, and long-term aging resulted in a sharper drop in ER. The reduction in moisture resistance of mixtures made by preaged asphalts could be observed primarily due to the decreased wettability of aged binders. Nevertheless, if the aging of asphalt occurred on the aggregate surface, the overall moisture resistance was also related to the contact time of asphalts and aggregates. Upon short-term aging, the wettability of asphalt associated with the coating quality was actually improved with contact time, and more asphalt could be absorbed into the pores of the aggregate. In other words, the contact area of the asphalt and aggregate continued to increase, contributing to an increased overall adhesion. In fact, the asphalt mixtures after short-term aging exhibited better moisture resistance, although the asphalt became deteriorated. However, the contact area could not further increase upon reaching the "perfect coating" while the surface free energy of asphalt continued to change with aging time. After long-term aging, the asphalts were heavily deteriorated and the stripping potential per unit area became overly high, which resulted in significant reduction in moisture resistance.