Background: Platelet-rich fibrin (PRF) is an autologous biomaterial that promotes tissue regeneration through sustained release of growth factors. Its role in accelerating bone healing in mandibular fractures, however, remains incompletely defined. This study evaluated the effect of PRF on bone regeneration following open reduction and internal fixation (ORIF) of bilateral mandibular fractures. Methods: A prospective split-mouth clinical trial was conducted at a single center between December 2023 and September 2025. Twenty patients with bilateral mandibular fractures were enrolled; each patient received PRF on one fracture side and conventional ORIF on the contralateral side. Bone density was quantified using Hounsfield units (HU) from preoperative and postoperative computed tomography scans at 2 weeks, 1 month, and 3 months. Statistical analysis employed a two-way repeated-measures analysis of variance with post hoc comparisons. Results: Eighteen patients completed the 3-month follow-up and were included in the final analysis. Bone density increased significantly over time in both sides (p< 0.001), with a significant side by time interaction (p< 0.001). At 3 months, PRF-treated sites demonstrated higher HU values (700.0± 152.1) than controls (567.8± 135.7), yielding a mean difference of 132.2 HU (p< 0.001, Cohen’s d= 0.94). No early intergroup differences or postoperative complications were observed. Conclusion Adjunctive use of PRF significantly enhanced bone density at 3 months without increasing complications. PRF appears to promote late-stage bone mineralization; however, larger multicenter studies with longer follow-up are required before recommending routine clinical implementation.