Purpose: The aim of the present systematic review with meta-analysis was to investigate the clinical effectiveness of EMD (enamel matrix derivative) using a minimally invasive surgical technique (MIST) or flapless approach for the treatment of severe periodontal probing depths. Materials and Methods: A systematic review of the literature including searches in PubMed/Medline, Cochrane Library, Google Scholar, and Grey Literature databases as well as manual searches was performed on September 1st, 2021. Studies utilising EMD in a non-surgical or minimally invasive approach were included. The eligibility criteria comprised randomised controlled trials (RCTs) comparing minimally-invasive/flapless approaches with/without EMD for the treatment of probing depths >5 mm. Results: From 1525 initial articles, 7 RCTs were included and 12 case series discussed. Three studies investigated a MIST approach, whereas 3 studies utilised a flapless approach. One study compared EMD with either a MIST or a flapless approach. The RCTs included ranged from 19–49 patients with at least 6 months of follow-up. While 5 of the studies included smokers, patients smoking >20 cigarettes/day were excluded from the study. The meta-analysis revealed that EMD with MIST improved recession coverage (REC) and bone fill (BF) when compared to MIST without EMD. However, no difference in CAL or PD was observed between MIST + EMD vs MIST without EMD. No statistically significant advantage was found for employing the EMD via the flapless approach. Conclusions: Implementing EMD in MIST procedures displayed statistically significant improvement in REC and BF when compared to MIST alone. These findings suggest that MIST in combination with EMD led to improved clinical outcomes while EMD employed in nonsurgical flapless therapy yielded no clinical benefits when compared to nonsurgical therapy alone without EMD. More research is needed to substantiate these findings.