Radicular cysts are the most common cystic lesions affecting the jaws. They arise from the epithelial remnants in the periodontal ligament as a result of the stimulus from periapical infection following pulpal necrosis. Treatment options to manage large periapical lesions range from nonsurgical root canal treatment or apical surgery to extraction. New approaches involve the use of local drug delivery systems based on microparticles/ nanoparticles made from biocompatible polymers along with surgical intervention. Such devices enable the introduction of antimicrobial agents or other drugs directly in the periradicular area or inside the root canal, and the prolonged release of constant concentrations of these agents for fast and better healing. The present case report illustrates the combined endodontic and surgical management of a large periapical cyst with local drug delivery as an adjunct.