Probing the mechanical behavior of the region formed between a nanoparticle reinforcement and a polymer matrix in a polymer nanocomposite structure, denoted as the “interphase”, is a main challenge as such regions are difficult to investigate by experimental methods. Here, we accurately characterize the heterogeneous mechanical behavior of polymer nanocomposites, focusing on polymer/nanofiller interphases via a combination of nanomechanical simulations and numerical homogenization techniques. Initially, the global mechanical performance of a glassy poly(ethylene oxide) polymer nanocomposite reinforced with silica nanoparticles is studied using detailed atomistic molecular dynamics simulations for 1.9% and 12.7% silica volume fractions. Next, the polymer/silica interphase thickness is identified by probing the polymer atom-based density distribution profile in the vicinity of the nanofiller at equilibrium. On the basis of this thickness, the interphase is subdivided to check the position-dependent change in mechanical properties. Then, using continuum mechanics and atomistic simulations, we proceed to compute the effective Young’s modulus and Poisson’s ratio of the polymer/nanoparticle interphase as function of the distance from the nanoparticle. In the last step, an inverse numerical homogenization model is proposed to predict the mechanical properties of the interphase on the basis of a comparison criteria with the data from MD. The results were found to be acceptable, raising the possibility of accurately and efficiently predicting interfacial properties in nanostructured materials.