Cephalexin, the first generation antibiotics has been employed for the treatment of infectious disease associated with skin and soft tissues, the urinary system, and the feet of diabetics. Cephalexin has been made into a novel nanosponge because topical formulations were not accessible and these preparations can improve skin permeability. Ethyl cellulose, polyvinyl alcohol, and Pluronic F68 were used to create various different cephalexin nanosponges employing the emulsion solvent evaporation method. Particle size and entrapment effectiveness were determined to be in the range of 200–400 nm and 88.5–95.6%, respectively.