This study focuses on the formulation and optimization of Olmesartan polymeric nanoparticles (PNs) to improve the bioavailability and stability of the antihypertensive drug. Polymeric nanoparticles offer advantages such as enhanced drug stability, improved absorption, and sustained release. The study employs techniques like nanoprecipitation and emulsion solvent evaporation for the synthesis of PLGA polymeric nanoparticles. The formulation parameters, including polymer type, concentration, surfactant selection, and processing conditions, are systematically varied and evaluated using statistical designs. The particle size and zeta potential of the nanoparticles are analyzed, and the optimized formulation, OPN5, is selected based on meeting the acceptance criteria for particle size and zeta potential. Stability studies are conducted on OPN5, and its performance is evaluated after storing for three months at 4°C. The results show slight changes in particle size, zeta potential, polydispersity index, drug encapsulation efficiency, and yield, indicating acceptable stability. The development and optimization of Olmesartan PNs have the potential to enhance the therapeutic efficacy of the drug by addressing its limitations in bioavailability and stability.