Due to an increasing rate of traffic volume and truckloads in recent years, asphalt binders are often modified with synthetic polymers to increase stiffness and sustain excessive heat during hot summer days. However, the cost of polymer-modified binders (PMBs) is significantly higher than unmodified binders. Nanoclays, on the other hand, are relatively inexpensive and naturally abundant, and have favorable intrinsic properties, such as nanoscopic size and high surface area. To this end, the research reported in this paper investigated moisture resistance properties of a commonly used Performance Grade (PG) 64-22 binder modified with different dosages of two selected nanoclays [(1) Cloisite 15 A, and (2) Cloisite 11B]. The state of dispersion of the nanoclay in the binder was examined using a scanning electron microscope and small-angle x-ray diffraction. The morphological analyses of scanning electron microscope scans and inter-gallery distances (-spacing values) of small-angle x-ray diffraction data of the two selected nanoclays are effective in evaluating the state of exfoliated microstructure of nanoclays in asphalt binders. In particular, the small-angle x-ray diffraction data of two of the tested samples [(1) 4% of Cloisite 11B, and (2) 6% of Cloisite 11B] showed fully exfoliated microstructure. Moisture resistance of nanoclay-modified binders was evaluated through the surface free energy (SFE) technique. The adhesive energies and compatibility ratios (CRs) of nanoclay-modified binder and selected aggregate (four acidic and four basic) systems were also evaluated. The total SFE increases when the asphalt binder is modified by nanoclays. When the asphalt binder is modified with nanoclays, the wetting ability decreases. A 4% Cloisite 15 A and a 6% Cloisite 11B (by the weight of the binder) showed the highest adhesive energy in maintaining good wetting ability, with different acidic and basic aggregates. The work-of-adhesion values under dry and wet conditions of nanoclay-modified binders were highly dependent on the nature (acidic or basic) of aggregate. The CR, an indicator of moisture resistance or bond strength in wet conditions, of the nanoclay-modified asphalt binder decreased for all aggregates except for granite, which showed a slight increase of the CR values. Thus, unless modified with an antistripping agent or other additives, nanoclay modified binders are expected to have poorer moisture resistance than the base binder. While maintaining a dosage level of 4% (by weight) nanoclay, Cloisite 15 A, consisting of smaller particle size than Cloisite 11B, is more compatible with different aggregates than Cloisite 11B. At a lower dosage level (2% by weight), Cloisite 11B is more compatible than Cloisite 15 A. Furthermore, the nanoclay technology is expected to be a cost saving approach, which can reduce the cost per metric ton of asphalt binder from 22–33% compared to the polymer-modified binders. Findings of this paper are expected to assist pavement professionals in evaluating moisture resistance of nanoclay-modified asphalt binders through a fundamental science approach.