The introduction of recombinant human growth and differentiation factors (rhGFs) for intrabony defects regeneration has represented a considerable breakthrough in recent years. However, they have been used in different concentrations, doses and combined with various scaffolds, and there is no evidence on which the most effective formulation for periodontal regeneration is. Therefore, we aimed to evaluate and rank the various formulations of such bioactive agents through network meta-analysis of clinical studies. The protocol registration was done on PROSPERO with registration ID CRD42020213753. To report NMA, we followed PRISMA guidelines and searched PUBMED, Embase, Web of Science and Cochrane Central electronic databases. Studies were screened based on specific inclusion criteria. Primary outcomes extracted from included studies were the most common indexes for periodontal regeneration (PPD, CAL, %bone filling). The NMA analysis included network plots, contribution plots, inconsistency plots (if eligible to form the loop), predictive interval plots, SUCRA rankings and multidimensional scale ranking (MDS) plots. SUCRA would demonstrate the rankings of multiple competing bioactive agents based on their best performance. Twelve clinical studies for qualitative and quantitative analysis were considered. Network meta-analysis found that rhFGF + hyaluronic acid was ranked highest in PPD and CAL outcome. rhPDGF-BB + β-tricalcium phosphate was ranked highest in the percentage of bone filling. In addition, all bioactive agents performed better than control groups without rhGFs. Despite clear benefits deriving from rhGFs for periodontal regeneration, the present results should be interpreted with caution due to several confounding factors affecting the outcome. Nevertheless, further well designed randomized clinical trials will allow establishing guidelines for an appropriate indication of the use of rhGFs.