A series of drug-loaded poly(methyl methacrylate) (PMMA) nanoparticles were prepared and studied as controlled release carrier of quercetin drug using a simple one-step differential microemulsion method. The polymer carriers were prepared in different monomer/surfactant ratios. The encapsulated PMMA nanoparticles were characterized by Fourier transform infrared spectroscopy, dynamic light scattering and transmission electron microscopy analysis. The particle size was obtained below 10 nm with spherical shape and narrow size distribution. In vitro drug release studies were performed using a dissolution medium such as sodium phosphate buffer saline simulating body fluids. Based on a full factorial 32 experimental design, nine formulations for quercetin-loaded PMMA nanoparticles were prepared and the molar ratio of monomer/surfactant and amount of initiator were considered as independent variables, while the encapsulation efficiency, solid content and drug release were taken into account as responses. Based on ANOVA analysis, with desirability factor of 0.952, the software F3 was suggested as an optimized formulation. This formulation was composed using a monomer/surfactant molar ratio of 3 and initiator amount of 0.02 g as independent variables, while the amounts of 71.10, 25.34, and 61.54%, in the order given, for encapsulation efficiency, solid content and drug release, were obtained as responses. To estimate release mechanism, the obtained cumulative release data were fitted to zero-order, first-order, Higuchi and Korsmeyer-Peppaskinetic models. In vitro release experiments in all cases revealed that the controlled release behavior followed from Korsmeyer-Peppas kinetic model exhibited non-Fickian diffusion mechanism. Consequently, this research offers useful pharmaceutical carriers with the purpose of providing prolonged release for targeting delivery.