Platelet concentrates have been widely used in regenerative medicine, including endodontics. The aim of this manuscript was to assess critically the efficacy of PRF in the treatment of endodontic periapical lesions in adult patients on the basis of the literature. The PICO approach was used to properly develop literature search strategies. The PubMed database was analyzed with the keywords: “((PRP) OR (PRF) OR (PRGF) OR (CGF)) AND (endodontic) AND ((treatment) OR (therapy))”. After screening of 155 results, 14 articles were included in this review. Different types of platelet concentrates are able to stimulate the processes of proliferation and differentiation of mesenchymal stem cells. Platelet rich fibrin (PRF) releases growth factors for at least 7 days at the application site. Growth factors and released cytokines stimulate the activity of osteoblasts. Moreover, the release of growth factors accelerates tissue regeneration by increasing the migration of fibroblasts. It was not possible to assess the efficacy of PRF supplementation in the treatment of endodontic periapical lesions in permanent, mature teeth with closed apexes, due to the lack of well-designed scientific research. Further studies are needed to analyze the effect of PRF on the healing processes in the periapical region.