Polymers represent a highly versatile material class and can be further enhanced to meet the requirements of highly demanding applications by adding filler particles. Particularly with nano-sized fillers, remarkable improvements in polymer nanocomposites’ (PNCs’) mechanical performance could be achieved experimentally. Since the outstanding mechanical properties of PNCs are mainly attributed to the matrix-filler interphase, a detailed understanding of this interphase is necessary to exploit the full potential of PNCs. To this end, the present work introduces a methodology to derive continuum mechanical models for PNCs based on molecular dynamics and thus combines the advantages of particle-based and continuum approaches. Although we use nano-silica-reinforced polystyrene as an example for our investigations, the methods can be easily transferred to other material pairings. First, we present a strategy to characterize the mechanical behavior of neat polymer and filler based on MD simulations. These insights enable us to subsequently calibrate appropriate continuum mechanical constitutive laws for the viscoplastic polymer and the anisotropic, elastic filler. Since the interphase cannot be investigated separately, we consider polystyrene-silica samples with two nanofillers at different filler distances. In order to realize comparable simulation setups, we employ an MD-FE coupling method to perform uniaxial tension simulations. The resulting overall force response and interparticle strain facilitate the identification of the inelastic property profiles within the interphase. This continuum mechanical interphase model reproduces the characteristic size effect of PNCs. Furthermore, the obtained constitutive descriptions for matrix, filler, and interphase form the prerequisite for analyzing representative volume elements (RVEs). Using these RVEs, we evaluate the influence of filler content and distribution on the nanocomposite’s overall stiffness. Consequently, this interdisciplinary work contributes significantly to understanding polymer nano-composites, especially the crucial matrix-filler interphase, and thus complements experimental insights. Moreover, the transfer of molecular-scale insights into continuum mechanical models forms an essential link between the chemistry and engineering communities for the numerical modeling of polymer nanocomposites.