The aim of this systemic review was to collate and analyze existing data from published literature sources to identify the current understanding of the role of epigenetic and biological biomarkers in periodontal disease and diagnostics. A comprehensive searching strategy was undertaken in Embase, Medline, The Dentistry and Oral Sciences and CINAHL databases. Grey literature searching strategies were also employed. Articles published in the English language between 2017–2020 were included. A total of 1014 studies were returned of which 15 studies were included. All included articles were cross-sectional, case–control studies. Relevant data were extracted according to various demographic and methodological factors including cohort size, oral biofluid sampled, number of examiners, smoking status and reported outcomes. A measure of the biomarker levels and corresponding significance were documented where possible. This review identified that exRNA has the greatest diagnostic potential, with four biomarkers (SPRR1A, lnc-TET3-2:1, FAM25A, CRCT1) displaying sensitivity of >71% and specificity of 100% in the assessed samples (p < 0.001) for gingivitis. This work also identifies the need for a unified approach to future research to draw meaningful comparison. Further investigations are warranted to definitively validate exRNA data and for the development of an exRNA-specific point-of-care diagnostic test.