Managing large cyst-like periapical lesions poses significant challenges, especially when nonsurgical treatment or retreatment options are ineffective. Despite its efficacy, decompression remains an underutilized minimally invasive alternative in modern dentistry. This case report describes the use of a Penrose drain for decompression following aspiration and irrigation to manage a large periapical lesion associated with a 56-year-old man's maxillary lateral incisor. The lesion had caused thinning and perforation of the facial and palatal cortical plates, as well as the inferior border of the nasal fossa. Cone-beam computed tomography was used to evaluate the lesion preoperatively and to assess the healing progress postoperatively. Complete 3-dimensional healing was observed after a subsequent root-end surgery performed 3.5 years post-decompression. This report suggests that decompression using a Penrose drain in combination with aspiration and irrigation could be a simple but effective modality for managing large cyst-like periapical lesions when nonsurgical endodontics are attempted and deemed ineffective.