Aim: This systematic review examined the additional effect of taking omega-3 supplements on periodontal therapy. Methods: The focused question was “What is the possible effect of omega-3 supplementation concomitant to non-surgical periodontal therapy on clinical periodontal parameters?” Databases Cochrane, Embase, Google Scholar, PubMed, and Web of Science (January-July 2021) were searched to identify appropriate studies. Randomized clinical trials (RCT) about non-surgical therapy with omega-3 supplementation, with at least 3 months of supplementation period were included. Cochrane risk of bias tool version 2 and Grading of Recommendations Assessment, Development, and Evaluation were used. Results: A total of 1556 studies were found, of which eight studies met the inclusion criteria. All eight studies evaluated periodontal probing depth and clinical attachment loss; plaque and gingival inflammation were evaluated in seven studies. High variety of omega-3 dosage, different study lengths, questionable results from periodontal therapy (including test and control groups), high risk of bias and moderate quality of evidence prevented a satisfactory conclusion regarding the benefits of omega-3 supplementation. The studies’ high heterogeneity avoided meta-analysis. Conclusion: Notwithstanding all limitations, the promising effects of omega-3 supplementation presented in two six-month studies encourage performing RCT with better-defined treatment protocols and greater methodological rigor.