Background <p>The aim of this study was to compare the effects of advanced platelet-rich-fibrin (A-PRF) and oral dexamethasone on postoperative complications in patients undergoing impacted mandibular third molar extraction.</p> Methods <p>This split-mouth, prospective, randomized-controlled study involved bilateral extraction of impacted mandibular third molars. A-PRF was applied to the extraction socket on one side, while postoperative oral dexamethasone was prescribed for the other side. Data were collected on pain, edema, trismus, and analgesic consumption. Intra-group and inter-group comparisons were performed. The Visual Analog Scale (VAS) was used for pain assessment. The patients were given a form to record their postoperative analgesic use. Pain assessments were conducted at postoperative 3, 6, 9, 12, 24&#xa0;h, and on Days 2, 3, 4, 5, 6, 7, 14, and 30. Maximum interincisal distance was measured for trismus evaluation, while facial measurements between specific points were taken for edema assessment. Trismus and edema measurements were conducted on postoperative Days 2, 7, 14, and 30.</p> Results <p>This study included 30 patients with bilateral impacted mandibular third molars (total of 60 extractions). The VAS scores were significantly lower on the side treated with oral dexamethasone compared to the A-PRF side at all measurement times (<i>p</i> &lt; 0.01). Considering edema evaluation, measurements were similar between both sides at all time points except on Day 2, when the A-PRF side showed significantly higher values (<i>p</i> = 0.001 and <i>p</i> &lt; 0.01). For trismus evaluation, maximum interincisal distance was significantly greater on the oral dexamethasone side on Days 2 and 7 compared to the A-PRF side (<i>p</i> = 0.001 and <i>p</i> &lt; 0.01). Analgesic consumption was significantly higher in the A-PRF group than in the oral dexamethasone group at all measured time points between 12&#xa0;h and Day 7 (<i>p</i> &lt; 0.01).</p> Conclusion <p>Oral dexamethasone appeared to be more effective than A-PRF in reducing postoperative complications. However, no significant difference was observed between the two groups in edema on Days 7, 14, and 30. Although not as effective as oral dexamethasone, A-PRF, being an autologous product with no side effects, can still be considered for reducing complications following impacted tooth extraction.</p> Trial Registration <p>The study was retrospectively registered at ClinicalTrials.gov with the number of NCT06823934, Registration date 02 June 2025.</p>