Endodontic microsurgery encompasses the use of microscopy, specialized instruments, and advanced imaging with cone-beam computed tomographic (CBCT) imaging. This treatment modality results in high clinical success rates and facilitates the enucleation of osteolytic lesions, the resection of apical root canal complexities harboring persistent bacterial biofilms, and the evaluation of possible root defects and fractures. However, there is the risk of injury to important anatomic structures, particularly when treating posterior teeth. Neurovascular bundles are among these structures at risk for injury. Fortunately, high-resolution CBCT scans can be used to detect these structures that are known to have a high anatomic variability. In addition, CBCT information can be combined with high-resolution intraoral scans to plan, design, and fabricate surgical guides to be used in a targeted endodontic microsurgery (TEMS) approach. We report 3 cases with previous endodontic treatment having persistent apical periodontitis that were treated with TEMS to avoid damage to the neurovascular bundles at risk of injury. In the first case, the palatal root of tooth #14 was adjacent to the greater palatine artery. In the second case, the mental nerve exited through 2 separate foramina close to the predictive osteotomy site for the mesial root of tooth #19. In the third case, the posterior superior alveolar artery was in close proximity to the mesiobuccal root of tooth #14. Collectively, these cases illustrate the diagnostic value of CBCT imaging for detecting neurovascular bundles and the use of TEMS to mitigate the risk of injury to these important structures. Thus, the combination of CBCT imaging and TEMS can potentially minimize the risk of intraoperative complications and postoperative sequelae while increasing the predictability of endodontic microsurgeries in complex cases.