Background Growth factors have been used with success in periodontal regeneration, especially in intrabony defects. Among those, the recombined form of fibroblast growth factor‐2 (rhFGF‐2) has been also examined. Objective To address the outcomes of periodontal regeneration using rhFGF‐2 alone or in combination with bone substitutes primarily in terms of Radiographic Bone Fill (RBF%) and secondary Probing Pocket Depth (PPD), and Probing Attachment Levels (PAL). Material and Methods A search in MEDLINE and EMBASE using the Ovid interface was conducted from 2000 up to and including the 12th of November 2022. Starting from the initially identified 1289 articles, 34 studies were selected for further analysis. Following the full‐text screening, 7 of the 34 studies met the inclusion criteria and thus were included in the systematic review after assessing their quality according to the Newcastle‐Ottawa scale (NOS). Clinical and radiographic results (bone gain, pocket depth, and clinical attachment level) after the application of FGF‐2 alone or in combination with different carriers were studied in patients with intrabony defects of at least one wall and pocket depth greater than 4 mm. Results Primary outcomes: RBF% was higher in studies using a combination of rhFGF‐2 and bone substitutes (74.6 ± 20.0%) compared to others using the specific growth factor alone or negative controls (22.7 ± 20.7%). In terms of secondary outcomes, the analysis failed to show an additional benefit from the use of the rhFGF‐2 alone or in combination with bone substitutes. Conclusion rhFGF‐2 can improve RBF% in the treatment of periodontal defects, especially when it is used in combination with a bone substitute.