Background: Large cyst-like periapical lesions are often managed initially with conventional nonsurgical root canal treatment. However, persistent clinical signs despite adequate disinfection and obturation may necessitate endodontic microsurgery. Careful case selection, advanced imaging, and modern microsurgical techniques are essential for predictable healing. Case Presentation: A 35-year-old male presented with pain, swelling, and a draining sinus tract in the maxillary right anterior region for one month, with a history of dental trauma ten years earlier. Clinical examination revealed tenderness to percussion, purulent discharge, and negative pulp sensibility responses in teeth 11 and 12, while tooth 13 exhibited an exaggerated lingering response suggestive of symptomatic irreversible pulpitis. Cone-beam computed tomography (CBCT) demonstrated a large cyst-like periapical lesion measuring 20.1 × 12.7 × 18.5 mm with buccal and palatal cortical plate perforation, extension to the nasal floor, and involvement of the nasopalatine canal. Conventional root canal treatment was performed for teeth 11, 12, and 13. Teeth 11 and 12 underwent sequential intracanal medication using calcium hydroxide and double antibiotic paste alternatively for 5 visits. Following successful canal drying and obturation, the persistent sinus tract and extensive osseous destruction warranted endodontic microsurgery. Apicoectomy and ultrasonic root-end preparation were performed under a dental operating microscope, followed by retrograde filling with Biodentine. The osseous defect was managed using sticky bone prepared with Osseograft® and injectable platelet-rich fibrin (i-PRF), covered with a platelet-rich fibrin (PRF) membrane. At six-month follow-up, the patient was asymptomatic, with resolution of the sinus tract and radiographic evidence of progressive periapical healing. Conclusion: This case demonstrates that endodontic microsurgery is a predictable treatment option for persistent large cyst-like periapical lesions following appropriate nonsurgical root canal treatment. Integration of CBCT-based diagnosis, microsurgical techniques, bioceramic root-end filling, and regenerative adjuncts may contribute to favorable clinical and radiographic outcomes in extensive periapical defects.