Third molar extraction is a common oral surgical procedure that can be accompanied by challenges in wound healing and bone regeneration. Materials such as bone substitute materials (BSMs) and platelet-rich fibrin (PRF) are often used to support socket regeneration. This prospective randomized controlled split-mouth clinical trial compared PRF application combined with BSM versus PRF alone in patients requiring bilateral third molar extraction. A total of 15 patients underwent standardized osteotomy procedures, with sockets filled either with PRF alone (control group) or with BSM + PRF on opposite sides (test group) under general anesthesia and with patients blinded to the treatment allocation. Postoperative pain and swelling were measured over 7 days using a visual analog scale and anatomical distance measurements, respectively. Bone regeneration was evaluated using cone beam computed tomography (CBCT) scans after an average healing period of six months, with results showing no significant differences between groups in terms of postoperative pain or swelling (n = 12; 3 patients were lost to randomization). However, CBCT imaging revealed covered socket residuum (CSR)—non-mineralized areas within the socket—in the PRF only group, whereas the BSM + PRF group demonstrated more homogeneous and mineralized bone formation throughout the extraction sites (n = 8; 5 patients were lost to follow-up). These non-mineralized areas represent covered socket residuum within the extraction sockets, which poses a clinical risk of infection and may negatively affect the dental health of the adjacent second molar. Based on the presented findings, we recommend combining BSM with PRF to support bone regeneration and regulate the postoperative pain and swelling following third molar extraction. Nevertheless, further research is required to determine the most suitable BSM type in this regard.