In this work, Layered Double Hydroxide (LDH) materials carrying the worldwide administered non-steroidal anti-inflammatory drug naproxen (NAP), and the sodium naproxenate salt (NaNAP) for comparison, were studied by computational approaches aiming to model the structure of hybrid LDH-drug and shed light on NAP intercalation process. Atomic modeling calculations were performed at the quantum mechanical level based on Density Functional Theory and classical force fields based on empirical interatomic potentials. LDH NAP materials were prepared by ion exchange reaction from Mg2Al(OH)6Cl and Zn2Al(OH)6Cl pristine phases. The characterization of the materials confirmed NAP intercalation and also the permanence of the pristine phases in the isolated materials after ion exchange. Crystallographic lattice parameters, elemental analysis, and TGA experimental results were then employed in the calculations, which revealed that NAP anions can completely neutralize the positive charge of the LDH layers: both Mg2Al and Zn2Al LDH structures could be optimized with all Cl− anions substituted by NAP. The drug assumed different dispositions in the NaNAP crystal or when intercalated into LDH. Additionally, infrared wavenumbers calculations agreed with the experimental results and showed useful to support LDH NAP bands assignment. The employed theoretical models to represent the structure of LDH NAP systems are expected to assist the interpretation of future experimental results and to be used as auxiliary tools to tune properties of LDH-drug pharmaceutical formulations.