This study was undertaken to evaluate the effects of reclaimed asphalt pavement (RAP) on moisture-induced damage potential of asphalt mixes using two different approaches: (i) micro-structural analysis of aggregate–asphalt bonding based on the surface free energy (SFE), and (ii) mechanical testing of asphalt mixes using retained indirect tensile strength ratio (TSR) and Hamburg wheel tracking (HWT). This study involved two phases. In the first phase, the SFE (non-polar, acidic and basic) components of a virgin PG 64-22 binder mixed with 0, 25, and 40 % of simulated RAP binder and aggregates (limestone, rhyolite, RAP extracted aggregate) were measured using a dynamic contact angle (DCA) device and a universal sorption device (USD), respectively. Thereafter, composite work of adhesion and composite work of debonding, and composite energy ratios for each combination of asphalt binder and aggregates were determined to assess the moisture-induced damage potential of the mixes containing different percentages of RAP (0, 25, and 40 %). In the second phase, the TSR and HWT tests were conducted on asphalt mixes containing different percentages of RAP (0, 25, and 40 %) to evaluate their moisture-induced damage potential. Both the methods showed that the moisture-induced damage potential decreased with increasing amount of RAP in asphalt mixes. A strong correlation was found to exist between the moisture-induced damage potential predicted using the micro-structural method and laboratory performance tests. It was found that the micro-structural energy approach, as a mechanistic framework, can be successfully used as an indicator of moisture-induced damage potential of the asphalt mixes. It is expected that the present study would be helpful in understanding the moisture-induced damage potential of flexible pavements containing RAP.