Background: Periodontal infrabony defects are challenging to treat due to their complex morphology and potential for disease progression. While open flap debridement (OFD) is a standard surgical approach, adjunctive biologic agents have emerged as promising tools to enhance regeneration. This systematic review and meta-analysis evaluated the clinical efficacy of three biologics—Enamel Matrix Derivative (EMD), Platelet-Rich Fibrin (PRF), and recombinant human Platelet-Derived Growth Factor-BB (rhPDGF-BB), with or without β-tricalcium phosphate (β-TCP)—when combined with OFD in the treatment of infrabony defects. Methods: A comprehensive search of PubMed, Embase, and Web of Science was conducted up to June 2023, following PRISMA guidelines. Randomized controlled trials comparing EMD, PRF, or rhPDGF-BB ± β-TCP with OFD alone or other comparators were included. Meta-analysis was performed using RevMan software, focusing on three primary outcomes: Clinical Attachment Level (CAL) gain, Probing Depth (PD) reduction, and Radiographic Bone Fill. Results: EMD and PRF demonstrated statistically significant CAL gain and PD reduction compared to OFD alone. rhPDGF-BB ± β-TCP showed the highest numerical gains in CAL and bone fill but did not reach statistical significance due to high heterogeneity. Funnel plot analysis showed relative symmetry, indicating minimal publication bias. Overall, biologics improved clinical outcomes and regenerative potential compared to conventional therapy. Conclusion: Adjunctive use of biologic agents, particularly EMD and PRF, enhances periodontal regeneration in infrabony defects beyond what is achieved with OFD alone. These findings support the integration of biologics into evidence-based regenerative periodontal protocols.