Conventional methods to quantify the moisture sensitivity of asphalt mixtures are based on the comparison of mechanical properties of the mix before and after a moisture-conditioning process. Although this approach consolidates the effect of material and mixture properties on moisture sensitivity, it does not identify the causes responsible for the poor or good performance of the mixture. In this study, surface free energy of asphalt binders and aggregates was used to derive energy parameters that quantify the moisture sensitivity of various combinations of materials. The moisture sensitivity of 12 asphalt mixtures carefully designed to represent a wide range of asphalt-aggregate interactions was measured in the laboratory under controlled conditions. Test results indicate that the moisture sensitivity of these mixtures correlates well with the energy parameters, which are based on the surface energy properties of the constituent materials. Incorporating the specific surface area of the aggregate into the energy parameters improved this correlation. The proposed energy parameters have the potential to serve as an effective tool by which to select material combinations that result in asphalt mixtures that are more resistant to moisture-induced damage.