Background Odontogenic cystic defects in the jaws are a common clinical challenge, often necessitating surgical intervention. Following enucleation, the management of the resulting bony defect is crucial for optimal healing. Calcium sulfate dihydrate has been proposed as an effective bone graft substitute due to its osteoconductive properties. This study aims to evaluate the efficacy of calcium sulfate dihydrate as a bone graft substitute in the management of odontogenic cystic defects following enucleation. Materials and Methods A total of 30 patients with odontogenic cystic defects in the jaws were included in this clinical study. All patients underwent enucleation of the cystic lesions, followed by the placement of calcium sulfate dihydrate as a bone graft substitute. The primary outcomes measured were bone regeneration, assessed radiographically and clinically at 1, 3, and 6 months postoperatively. Secondary outcomes included patient-reported pain and functional recovery. Radiographic evaluation was performed using cone-beam computed tomography (CBCT) to quantify bone density changes over time. Results The study observed significant bone regeneration in the treated sites. At the 1-month follow-up, radiographic analysis showed an average bone density increase of 20% from baseline. By the 3-month mark, bone density had improved by 45%, and by 6 months, the improvement reached 75% compared to baseline measurements. Clinically, all patients reported minimal postoperative pain, with an average pain score of 2 on a Visual Analog Scale (VAS) at 1 week postoperatively, decreasing to 0 by the 3-month follow-up. Functional recovery was noted to be excellent, with patients resuming normal masticatory functions within 4 weeks post-surgery. Conclusion Calcium sulfate dihydrate is an effective bone graft substitute for the management of odontogenic cystic defects following enucleation. The material demonstrated excellent osteoconductive properties, leading to significant bone regeneration and minimal postoperative complications. These findings suggest that calcium sulfate dihydrate can be a valuable addition to the armamentarium for oral and maxillofacial surgeons dealing with cystic jaw defects.