Background: Apical surgery can address periapical pathologies when conventional endodontic treatments fail. Advanced platelet-rich fibrin (A-PRF) has emerged as a regenerative material with the potential to enhance healing in periapical surgery. In this study, we evaluated the effect of A-PRF on periapical lesion healing using cone beam computed tomography (CBCT). Methods: A randomized controlled trial at Rīga Stradiņš University Institute of Stomatology included 43 participants (15 males, 28 females; mean age: 44 years) with periradicular lesions. Participants were divided into experimental and control groups. Baseline and follow-up CBCT imaging assessed lesion volumes at 6 and 12 months post-surgery. Results: Mean lesion volumes significantly decreased from 431.4 mm³ at baseline to 102.8 mm³ at 6 months and 49.2 mm³ at 12 months (p < 0.001). A-PRF did not significantly reduce the lesion sizes compared to the controls (p = 0.043), but was associated with reduced inflammation and enhanced soft tissue healing. Key confounders included gender and baseline lesion volume, with males exhibiting smaller lesion sizes postoperatively. Conclusions: The results suggest that A-PRF may not offer a significant advantage in terms of reducing defect size or improving radiographic resolution.