This systematic review aimed to generate evidence on role of potent markers of inflammation [cytokines, chemokines, their associated receptors and antagonists] following the application of orthodontic forces. Subsequent to registration with PROSPERO, literature search followed a predetermined search strategy to key databases along with hand search (HS). Seventy-seven articles from PubMed (P), 637 from Scopus (S), 51 from Embase (E), and 3 from hand search (HS) were identified. A total of 39 articles were shortlisted that met strict inclusion and exclusion criteria and quality assessment. Each study was evaluated for participant characteristics, study design, oral hygiene regimen, and gingival crevicular fluid (GCF) handling. Among these studies, biomarkers in the order of frequency were interleukin (IL)-1β (N=21), tumor necrosis factor (TNF)-α (N=10), IL-8,IL-6(N=8), receptor activator of nuclear factor kappa-B ligand (RANKL) (N=7), monocyte chemoattractant protein (MCP)-1 (N=3), IL-2 (N=4), IL-4, IL-10, RANTES (N=2), IL-1, IL-5, IL-1α, IP-10, osteopontin (OPN) (N=1) and receptors and their antagonists in the order of osteoprotegerin (OPG) (N=8), IL-1RA (N=5), and RANK (N=1). Results revealed an immediate release of inflammatory bone-resorptive mediators, IL-1β and TNF-α, where IL-1β increased as early as 1 min to 1 h reaching peak at 24 h while TNF-α increased at 1 h or 1 day. This was accompanied by a fall in bone-protective mediator (OPG) levels at 1 h and 24 h after orthodontic force application. Continuous forces were accompanied by a decrease in mediator levels after attaining peak levels (most commonly at 24 h) while repeated activations in interrupted force upregulated their secretion. Significant correlations of IL-1β levels with pain intensity, rate of orthodontic tooth movement (OTM) and of activity index (AI) (IL-1β/IL-1RA) with velocity of tooth movement and growth status of individuals have also been deduced. A greater AI and RANKL/OPG ratio was seen in juveniles as compared to adults or non-growers that were associated with faster rate of OTM in juveniles. None of the studies addressed the effect of estrous cycle in female subjects. Lack of homogeneity in several parameters calls for a better controlled research on the biology of OTM.