This study reports the development of a novel formulation of a polymeric nanoparticls (NPs) with the drug Promazine hydrochloride (PRO), a hydrophobic molecule, dispersed in biodegradable polymeric matrix of poly (DLlactide- co-glycolide) (PLGA) by using emulsion-solvent evaporation method at the temperature T = 298.15 K. Spherical NPs with controlled size were designed. PRO was capsulated into nanoparticles with theoretical drug loading (TDL) varying from 10 to 30% (w/w). The effects of TDL, of poly(vinyl alcohol) (PVA) concentration, of PLGA concentration in organic phase, the effect of power of sonication and of pH of aqueous phase were studied. After lyophilization of PRO-loaded nanoparticles, the average size, Zeta potential, and polydispersity index at TDL 30% were 350 ± 22 nm, −18.7 ± 2.0 mV, and 0.18 ± 0.04, respectively (at TDL 30%, PLGA content 1.3 % w/v and pH = 9). The maximum drug encapsulation efficiency and drug loading capacity were 32.74 ± 0.54% (w/w) and 19.13 ± 0.38 %, respectively (at TDL 30%, PLGA content 1.3% w/v and pH = 9). Scanning electron microscopy studies showed spherical and smoth shape of drug-loaded nanoparticles. Solid lyophilized NPs were evaluated for in vitro release in phosphate–buffered saline (pH = 7.4) by using dialysis bags. Parameters for the release process showed that both the initial PLGA content and energy of sonication have no significant influence on PRO release from NPs.