To evaluate the effect of platelet-rich fibrin alone or in combination with different biomaterials for the treatment of periodontal intra-bony defect. Up to April 2022, Cochrane library, Medline, EMBASE, and Web of Science databases were searched for randomized clinical trials. The outcomes of interest were probing pocket depth reduction, clinical attachment level gain, bone gain, and bone defect depth reduction. Bayesian network meta-analysis with 95% credible intervals was calculated. Thirty-eight studies with 1157 participants were included. Platelet-rich fibrin alone or platelet-rich fibrin +biomaterials showed a statistically significant difference when compared with open flap debridement (p < 0.05, low to high certainty evidence). Neither biomaterials alone nor platelet-rich fibrin +biomaterials showed a statistically significant difference when compared to platelet-rich fibrin alone (p > 0.05, very low to high certainty evidence). Platelet-rich fibrin +biomaterials showed insignificant differences as compared to biomaterials alone (p > 0.05, very low to high certainty evidence). Allograft +collagen membrane ranked the best in probing pocket depth reduction while platelet-rich fibrin +hydroxyapatite ranked the best in bone gain. It seems that (1) platelet-rich fibrin with/without biomaterials were more effective than open flap debridement. (2) Platelet-rich fibrin alone provides a comparable effect to biomaterials alone and platelet-rich fibrin +biomaterials. (3) Platelet-rich fibrin +biomaterials provide a comparable effect to biomaterials alone. Although allograft +collagen membrane and platelet-rich fibrin +hydroxyapatite ranked the best in terms of probing pocket depth reduction and bone gain respectively, the difference between different regenerative therapies remains insignificant, and therefore, further studies are still needed to confirm these results.