, optimization, characterization, and cytotoxic studies of NAR nanoparticles (NPs) to against pancreatic cancer. The sonication tailored Naringenin (NARG)-loaded poly (lactide-co-glycolic acid) (PLGA) NPs was fabricated for potential cytotoxic effect against pancreatic cancer. NARG NPs were prepared by emulsion-diffusion evaporation technique applying BoxBehnken experimental design based on three-level and three-factors. The effect of independent variables surfactant concentration (), polymer concentration (), and sonication time () were studied on responses particle size (), and drug release % (). NPs characterized for particles size and size distribution, polydispersity index (PDI), zeta potential, transmission electron microscope (TEM), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimeter (DSC), and X-ray diffraction (XRD) studies. Further, the studies was fitted to various drug release kinetic model and cytotoxicity evaluated . The nanosized particles were spherical, uniform with an average size of 150.45 ± 12.45 nm, PDI value 0.132 ± 0.026, zeta potential -20.5 ± 2.5 mV, and cumulative percentage release 85.67 ± 6.23%. release of NARG from nanoparticle evaluated initially burst followed by sustained release behavior. The Higuchi was best fitted model to drug release from NARG NPs. The cytotoxicity study of NARG NPs apparently showed higher cytotoxic effect over free NARG ( 0.05). The stability study of optimized formulation revealed no significant physico-chemical changes during 3 months. Thus, NARG-loaded NPs gave ameliorated anticancer effect over plain NARG.