The objective of this systematic review was to test the hypothesis of no difference in recovery following surgical removal of mandibular third molars with the application of advanced platelet-rich fibrin (A-PRF) in the extraction socket compared with alternative biomaterials or natural wound healing. A search of MEDLINE (PubMed), Embase, Cochrane Library, and Scopus was conducted. Human randomized controlled trials published in English up until December 31, 2020 were included. Outcome measures were pain, facial swelling, trismus, soft tissue healing, alveolar osteitis, and quality of life; these were evaluated by descriptive statistics and meta-analysis including 95% confidence intervals (CI). Four studies with a low or moderate risk of bias fulfilled the inclusion criteria. A-PRF resulted in significantly lower pain scores when compared with leucocyte platelet-rich fibrin or natural wound healing after 2 days (-16.8, 95% CI -18.9 to -14.7), 3 days (-12.1, 95% CI -13.4 to -10.7), and 7 days (-1.9, 95% CI -2.9 to -0.9). A-PRF seems to have a negligible effect on facial swelling and trismus and some beneficial effect on soft tissue healing. Alveolar osteitis and quality of life were not assessed. The included studies were characterized by considerable heterogeneity and confounding variables. Thus, the level of evidence appears to be inadequate for clinical recommendations according to the focused question.