Objectives: The goal of this study was to evaluate the impact of enamel matrix derivative (EMD) on periodontal healing after root coverage (RC) surgery, involving CAF in combination with SCTG, and to assess the molecular profile, verifying the inflammation level in early stage (1 and 2 weeks). Materials and methods: Thirty-two recessions (RT1) were submitted to periodontal surgery with (test) or without (control) EMD. The clinical parameters analyzed on the day of surgery and 6 months after the surgical procedure were as follows: recession height and width, keratinized tissue height, percentual root coverage, and the gingival thickness of keratinized tissue. Moreover, the main inflammatory biomarkers and growth factors (IL-1β, IL-6, IL-8, FGF, MIP-1α and β, PDGF, TNF-α, and VEGF) were evaluated at baseline, 7, and 14 days after procedures. Results: The average root coverage was significantly higher in the test group as compared to the control group (86% vs. 66%, p = 0.008). The test side had significantly lesser final RH compared to the control side (p = 0.01). Also, there was a significant reduction of RW in both groups, with more significant results in the test group. KTH and GT were not significantly different at any time and group. After 14 days, the immunological analysis showed an increase of VEGF (p = 0.03) on the test group compared to the control side. Conclusion: The use of EMD in RC surgeries resulted in a significantly higher RC, as well as a significant increase in VEGF expression, suggesting that EMD may contribute to the angiogenic and healing process. Clinical relevance: EMD provided better results in root coverage treatment when associated with CAF and SCTG, beyond a greater releasing of angiogenic growth factor (VEGF), which enhanced the result.