This study provides an analysis of the dissolution mechanism of poorly water‐soluble drugs, indomethacin (IND) and naproxen (NAP), from polyvinyl acetate (PVAc) and polyvinylpyrrolidone/vinyl acetate 64 (PVPVA 64) formulations under the combination of the Perturbed‐Chain Statistical Associating Fluid Theory (PC‐SAFT) and a chemical‐potential‐gradient model. Moreover, the dissolution kinetics of both drugs from these polymeric formulations were modeled in conformity with the in vitro experimental data obtained by means of a rotating disk system (USP II). The combination of the thermodynamic model PC‐SAFT and a chemical‐potential‐gradient model was demonstrated to be an efficient approach to explain the drug dissolution mechanism from the drug/PVAc and PVPVA 64 formulations. These results have implications in reducing experimental time and resources for the sustained dissolution kinetics profile determination without compromising accuracy, in particular for the system of the drug/PVAc formulation when obtaining continuous drug dissolution in this work.