Platelet rich fibrin (PRF) is an autologous biomaterial and has many clinical applications. It is produced without the addition of anticoagulant and with no gelling agent, through the immediate centrifugation of blood after collection. The effect of PRF on post-surgical pain is unclear. Thus the aim of this systematic review was to assess whether PRF was effective in controlling pain after the extraction of bilateral mandibular third molars. A comprehensive literature search was performed for articles published from January 2000 to January 2021 in the PubMed, PubMed Central, Directory of Open Access Journals (DOAJ), Campbell systematic review, Scopus, Cochrane review, Embase and Google scholar. Randomized clinical trials with PRF used as one of the comparison groups PRF after extraction and articles assessing pain as an outcomes measure were included for the systematic review. Results: A total of 160 records were found by preliminary screening through database search and 30 records were retrieved by additional sources, of which eleven were selected for qualitative analysis and four for quantitative analysis. A meta-analysis was performed only for pain, due to the considerable heterogeneity among studies for the other outcome variables. The overall quality of evidence was low for all outcomes of included studies. In these studies pain was assessed using a visual analog scale ranging from 0 (no pain) to 10 (most severe pain) point scale. Post-operative pain on day 1, 3 and 7 showed statistically significant difference between the PRF and non-PRF groups. In conclusion PRF administered after third molar extraction significantly reduced pain. But, further randomized controlled trials with larger cases and well-designed models are essential to validate the current findings.