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Objective: The objective of the present study was to develop and optimize Astragalin-loaded polymeric nanoparticles (AST-NPs) using a central composite factorial design (CCD). Methods: AST-NPs were prepared by the dialysis method. CCD was employed to study the influence of formulation factors, polymer concentration, aqueous organic phase ratio, and process parameter stirring time on dependent physicochemical characteristics, particle size, zeta potential, and percentage entrapment efficiency (%EE) of the drugs. The optimized formulation was evaluated for in vitro release studies and subjected to stability studies. Results: Polymer concentration and process parameters were optimized to produce nanoparticles with desired parameters. The prepared NPs were characterized by Fourier transmission infrared (FT-IR), differential scanning calorimetry (DSC), drug loading, entrapment efficiency, particle size, zeta potential, and in vitro studies. FT-IR and DSC studies indicated that there was no interaction between the drug and polymer. The optimized NPs exhibits stability. Optimized NPs exhibited spherical and porous surfaces with a mean PS of 118 nm, the zeta potential of-25 mV, and %EE of 89%. Conclusion: Astragalin-loaded nanoparticles prepared with optimized formulation composition and process parameters.