The aim of this article was to present a two-step procedure for treating two large periapical lesions located near the maxillary sinus. The first lesion measuring 7.1 mm by 6.1 mm by 5.9 mm was located around the apices of both upper right premolars and was perforating the alveolar bone. The second lesion, measuring 13.7 mm by 16.3 mm by 12.5 mm, was located around all the roots of the first upper right molar. The first step of the procedure involved single-session endodontic treatment. The second step involved endodontic microsurgery. To plan the microsurgery, a Cone Beam Computed Tomography image and an intraoral scan were taken, and a surgical guide was printed to enhance the outcome of the surgery. During the surgical procedure, a 3D-printed guide for the window preparation in the alveolar bone was created with a piezosurgery unit. Next, a microsurgical procedure under magnification with a microscope, retro-preparation, and retrofilling with bioceramic material and platelet rich fibrin were placed in the chamber after the apicectomy. A control cone-beam computed tomography (CBCT) taken 8 months after the treatment revealed full healing in the treated areas. Proper planning, novel technologies, biological approach and precise treatment allowed clinicians to successfully heal both periapical lesions.