Moisture damage of asphalt concrete is defined as the loss of strength and stability caused by the active presence of moisture. The most common technique to mitigate moisture damage is using additives or modifiers with the asphalt binder or the aggregate. Various additives and modifiers are used to enhance the performance of asphalt mixtures. However, some of these additives/modifiers may affect the moisture susceptibility of the asphaltic mixtures. The objective of this study was to investigate the effect, if any, of various additives and modifiers on the moisture susceptibility of asphalt concrete. Additives and modifiers included in this study were selected as those most commonly used in Illinois: liquid anti-strip (LAS), styrene butadiene styrene (SBS), polyphosphoric acid (PPA), and hydrated lime. Two mixtures exhibiting failed tensile strength ratio (TSR) results were selected for testing. Mixture-level lab tests were conducted including modified AASHTO T283 Lottman test with five freezing and thawing (FT) cycles, the Hamburg wheel tracking test, and a fracture test using semi-circular bending (SCB) specimens. The modified AASHTO T283 Lottman tests showed that LAS and hydrated lime improved moisture damage control of the asphalt mixes. In the wheel tracking tests, mixes with SBS-modified binder and mixes with hydrated lime provided the least rutting potential. The fracture tests generally showed that mixes with either hydrated lime or LAS had the best relative performance. Component-level tests were conducted including the direct adhesion test (DAT) and contact angle test to determine surface free energy (SFE). Results of SFE values and DAT parameters were in agreement with the results of mixture-level tests: LAS and hydrated lime generally help to mitigate a mixture’s susceptibility to moisture. Full-scale test sections were built and exposed to accelerated load testing. Although not all full-scale sections met the lab-mix design volumetrics, the control mix and the mixes with LAS and SBS had similar mixture composition compared with the labprepared mixes. This study found that LAS and hydrated lime might reduce moisture susceptibility of asphalt mixes. However, PPA may need to be used with another moisture control additive or modifier in order to avoid adverse effects on an asphalt mixture. The study also found that surface free energy values can be used to identify aggregate–binder compatibility with respect to moisture damage.