Background: The aim of this systematic review was to assess the efficacy of three biologics, namely autologous blood-derived products (ABPs), enamel matrix derivatives (EMD) and recombinant human platelet-derived growth factor BB (rhPDGF-BB), in root coverage and gingival augmentation therapy. Methods: The protocol of this PRISMA 2020-compliant systematic review was registered in PROSPERO (CRD42021285917). After study selection, data of interest were extracted. A network meta-analysis (NMA) was conducted to assess the effect of different surgical interventions on the main clinical outcomes of interest (i.e., mean root coverage [MRC%], complete root coverage [CRC%], keratinized tissue width [KTW], gingival thickness [GT] change, and recession depth [RD] reduction).Results: A total of 48 trials reported in 55 articles were selected. All studies reported on the treatment of gingival recession defects for root coverage purposes. Forty-six treatment arms from 24 trials were included in the NMA. These arms consisted of treatment with coronally advanced flap (CAF) alone, EMD + CAF, platelet-rich fibrin (PRF) + CAF, and subepithelial connective tissue graft (SCTG) + CAF. Regarding MRC%, SCTG+CAF was associated with a significant higher estimate (13.41%, 95% CI [8.06-18.75], P < 0.01), while EMD+CAF (6.68%, 95% CI [−0.03 to 13.4], P = 0.061) and PRF+CAF (1.03%, 95% CI [−5.65 to 7.72], P = 0.71) failed to show statistically significant differences compared with CAF alone (control group) or with each other. Similarly, only SCTG+CAF led to a significantly higher CRC% (14.41%, 95% CI [4.21 to 24.61], P < 0.01), while treatment arms EMD + CAF (13.48%, 95% CI [−3.34 to 30.32], P = 0.11) and PRF+CAF (-0.91%, 95% CI [−15.38, 13.57], p = 0.81) did not show significant differences compared with CAF alone or with each other. Differences in the CI of PRF+CAF (symmetrical around a zero adjunctive effect) and EMD+CAF (nonsymmetrical) suggest that EMD could have some additional value compared with PRF. Treatment with SCTG+CAF led to a statistically significant higher RD reduction (-0.39 mm, 95% CI [−0.55 to 0.22], P < 0.01), however EMD+CAF