Platelet-rich fibrin has become increasingly popular in recent years due to its remarkable capacity to accelerate the post-surgery wound healing process, reduce inflammation, and promote tissue repair. This study aimed to perform a meta-analysis to evaluate the effect of platelet-rich fibrin in mixture form with bone substitute, as a membrane, or in combination. A comprehensive search using a combination of controlled vocabulary (MeSH) and free-text terms was undertaken by two reviewers to identify published randomized clinical trials. Three major electronic databases (Medline via PubMed, Cochrane database, and Embase) and the clinical trials registry (clinicaltrials.gov) were searched up to 9 July 2023. The results of the meta-analysis showed that the pooled standardized mean difference of probing depth for platelet-rich fibrin was 0.61 (95% CI, 0.33 to 0.88). The results of the meta-analysis showed that the mean difference in clinical attachment level for platelet-rich fibrin was 0.68 (95% CI, 0.35 to 1.01). The results of the meta-analysis showed that the mean difference in bone fill for platelet-rich fibrin was 0.50 (95% CI, 0.23 to 0.78). In conclusion, the study found that platelet-rich fibrin was effective as adjunct to periodontal regeneration.