Indomethacin, a potent nonsteroidal anti-inflammatory drug (NSAID), is typically used for chronic inflammatory arthritis. However, patients receiving Indomethacin often experience gastrointestinal side effects. Thus, the design of targeted delivery formulations to reduce side effects of NSAIDs continues to be a focus of current research. In this regard, enteric nanoparticles have been recognized as a potential system to reduce gastrointestinal irritations. The aim of this study was to apply a two-level factorial design with three factors to the formulation of indomethacin-loaded nanoparticles. The effect of the polymer matrix and the surfactant on encapsulation efficiency was estimated. Statistical analysis of multilevel factorial design has shown 7 significance effects on evaluated response (95% confidence level), while PEG had shown the greater influence due to its co-surfactant behavior. Moreover, the process yield, particle morphology, and in vitro dissolution profile of the nanoparticles have been evaluated.