This study aimed to enhance the residence time of penciclovir on the skin by developing controlled-release microsponges to improve therapeutic efficacy for the treatment of cold sores. Microsponges were prepared using the quasi-emulsion solvent diffusion method. Ethyl cellulose was selected as the internal phase polymer, and dichloromethane was chosen as the solvent based on preliminary studies. A 3 full factorial design was employed to optimize the formulation, with polyvinyl alcohol as the stabilizer in the external phase. The optimized formulation achieved an entrapment efficiency of 76.56%, particle size of 64.12 µm, and prolonged drug release over 15 h. SEM analysis confirmed spherical, porous microsponge morphology, while stability studies demonstrated consistent performance over 3 months with an F2 value of 84.79, indicating formulation stability. The study successfully developed penciclovir-loaded microsponges with high entrapment efficiency and prolonged drug release characteristics. The formulation demonstrated prolonged drug release characteristics, indicating potential suitability for controlled-release topical application.