To evaluate the local and systemic application of photobiomodulation (PBM) to reduce pain after third molar extraction. PBM has been applied locally to reduce pain after third molar extraction, but there are no published studies evaluating its systemic application for this purpose. Thirty patients with two erupted third molars indicated for extraction were included in this split-mouth clinical trial. Extractions were performed 3 weeks apart in each patient, with one extraction socket being randomly assigned to local and systemic PBM (PBM group) and the other to no PBM (control group). Postoperative analgesia consisted of oral acetaminophen for 3 days. Outcomes included pain (visual analog scale), swelling, and quality of life (14-item Oral Health Impact Profile) assessed before and immediately, 24 h, 48 h, and 7 days after extraction. Results were analyzed by Kruskal-Wallis test, followed by Student-Newman-Keuls test. In the control group, pain increased significantly at 24 and 48 h after extraction (p = 0.0000), decreasing after 7 days (before: 0.36; immediately after: 1.06; 24 h: 4.26; 48 h: 2.53; 7 days: 0.36). In the PBM group, patients reported no pain at all time points, indicating effectiveness of local and systemic PBM in relieving pain after third molar extraction (p = 0.2151) (before: 0.30; immediately after: 0.36; 24 h: 0.86; 48 h: 0.30; 7 days: 0.03). PBM also had a modulatory effect on the inflammatory process and improved comfort after extraction. Combined local and systemic PBM can be useful for pain relief, swelling control, and quality-of-life improvement in patients undergoing third molar extraction.