In the context of polymer-based nanocomposites containing layered nanofillers, the achievement of good extents of dispersion and distribution of the embedded nanoparticles and, even more, the obtainment of intercalated and/or exfoliated structures through melt compounding still represents a persistent challenge, especially in the case of anionic layered double hydroxides (LDHs)-containing systems and non-polar polymeric matrices. In this work, a simulation approach is proposed to evaluate the influence of the processing conditions on the morphology of polypropylene (PP)-based nanocomposites containing organomodified LDHs. In particular, the effect of the screw rotation speed and the feed rate on the final microstructure of the materials formulated through melt compounding in a twin-screw extruder was assessed. The rheological and morphological characterizations demonstrated that a more homogeneous morphology was achieved when high levels of both exploited processing parameters are selected. The results coming from the simulation of the processing were used to establish some relationships between the flow parameters and the microstructure of the nanocomposites, demonstrating that low residence times coupled with high local shear rates are required to ensure the achievement of homogenous morphologies, likely involving the occurrence of intercalation phenomena.