Background: The aim of the systematic review was to evaluate the effect of periodontal interventions on the diversity and composition of periodontal microbiota assessed by high throughput sequencing (HTS) metagenomics analysis. Methods: An electronic search of all relevant databases was conducted from database inception to May 2021 by two independent reviewers. All clinical trials that evaluated the effect of periodontal interventions on the gingival microbiota through HTS were selected. The measures of alpha diversity was used as primary outcome; richness, Shannon diversity index, and the Chao1 index, whereas relative abundances of bacterial genera was considered as secondary outcome. The Robvis tool was used to assess the risk of bias. Results: Overall, 19 studies were eligible for the systematic review, of which 10 studies were included in the meta-analysis. Periodontal intervention for test group resulted in decrease in Shannon’s diversity, richness and Chao I index as observed from baseline to post-treatment. The most common genera found to increase after periodontal therapy were Rothia, Actinomyces, Streptococcus, Veillonella and Hemophilus and Porphyromonas, Tannerella, Fusobacterium, and Treponema decreased after periodontal therapy. Conclusion: Periodontal interventions may decrease the bacterial diversity and richness and alter the composition of oral microbiota in the short-term. Periodontal microbiota signatures could potentially be used for the assessment of periodontal intervention in the future. Further studies should implement methodological consistency to provide a more quantitative and mechanistic understanding of these approaches.