The aim of this article was to evaluate the potential of poly lactide-coglycolide (PLGA) nanoparticles (NPs) as carriers for controlling release of doxorubicin (DOX) via a spray drying technique. The challenge was to entrap a hydrophilic molecule into a lipophilic core molecule of PLGA. To achieve this objective, we modified conventional approach of drug loading to spray drying technique. The eight formulations of nanoparticles were prepared by modified double emulsion and solvent evaporation technique followed by spray drying using 2(3) factorial designs. PLGA (A) and PVA (B) and stirring speed (C) were used as independent variables where particle size (Y-1), entrapment efficiency (Y-2) and percentage of drug release at the 32 hour (Y-3) were taken as dependant variables. The results showed that the method is easy and efficient for the entrapment of the drug as well as the formation of spherical nanoparticles. This modification improved DOX entrapment efficiency relative to controls real loadings up to 40%. The in vitro release studies indicated the DOX loaded PLGA nanoparticles provide controlled drug release over a period of 32h. Hence, this investigation demonstrated the potential of the experimental design in understanding the effect of the formulation variables on the quality of DOX-PLGA nanoparticles.