Numerous plastic products are manufactured by processing techniques that enable the combination of individual polymeric materials within multilayer structures (e.g., co-extrusion, co-injection molding, and extrusion lamination) to obtain tailored properties. Providing sufficient adhesion between the single layers is of major importance. For a wide range of polymeric material combinations, interdiffusion of the macromolecules represents the predominating mechanism for adhesion. Understanding the interdiffusion process and predicting concentration profiles and hence resulting interphase thickness under certain processing conditions (e.g., contact time, interfacial temperature) contributes to efficient manufacturing processes and multilayer plastic products optimized to sophisticated applications. In this work, we investigate the formation of an interdiffusion layer (interphase) between two individual polymer melts by modeling the developing concentration profiles across the interphase and the resulting mutual interpenetration depth numerically. The two melt layers involved are approximated as semi-infinite bodies and the interdiffusion process is modeled based on Fick’s diffusion theory considering concentration dependent interdiffusion coefficients. To include the compatibility between different polymer melts, the interaction theory according to Flory and Huggins is applied. Further, all independent influencing parameters that govern the interdiffusion process are identified by transforming the diffusion equation into dimensionless representation. By varying these characteristic dimensionless parameters within particular ranges and numerically solving the partial differential equations, we analyzed their influence on the formation of the interphase and the final interdiffusion layer thickness.