Externally bonded fiber-reinforced polymer (FRP) composites are extensively used for repair and strengthening of concrete structures. The longevity of FRP repairs depends primarily on the durability of adhesive bonds between FRP and the underlying concrete substrate, which is established through epoxy adhesives. In this study, the effect of hygrothermal conditioning by water immersion on epoxy-cement paste interphase was characterized via site-specific nanoindentation. Reduced modulus and hardness were measured across the interphase for a dry and conditioned (water immersion at 30 °C for 4 weeks) cement paste-epoxy sample. The statistical nanoindentation approach, based on Gaussian mixtures decomposition, was used to determine the nanomechanical properties of distinct material phases in the interphase. The results confirm that hygrothermal conditioning by water immersion degrades the nanomechanical properties of the bulk epoxy, interphase, and bulk cement paste. Degradation in epoxy properties is explained by the plasticization of the epoxy due to moisture conditioning. The reduction in nanomechanical properties of interphase and bulk cement paste is primarily accredited to decalcification (also known as ‘calcium leaching’) processes induced by exposure to low-pH water environment.