BACKGROUND: Diabetes mellitus (DM)-associated hyperinflammatory host response significantly provokes periodontal tissue destruction. In this context, the support of nonsurgical periodontal therapy in diabetics with host modulation agents is a current field of study. This clinical study aims to investigate the clinical efficacy of melatonin supplementation and discuss its possible biological mechanisms in nonsurgical periodontal treatment in patients with DM and periodontitis through some fundamental markers. METHODS: In this randomized controlled and single-blind study, 27 of 55 diabetic patients with periodontitis (stage III/IV and grade C) underwent full-mouth scaling and root planing (fmSRP) alone and 28 patients underwent melatonin administration (6 mg daily, 30 days) in addition to fmSRP (full-mouth scaling and root planing plus melatonin, fmSRP-mel). The potential therapeutic contribution of melatonin was evaluated clinically and biochemically (gingival crevicular fluid RANKL, OPG, MMP-8, and serum IL-1β levels) at 3rd and 6th months. RESULTS: Melatonin (tablet, 6 mg daily, 30 days) did not cause any local or systemic side effects. fmSRP alone resulted in significant reduction in serum IL-1β levels, pocket depths, gingival inflammation, and gingival crevicular fluid RANKL and MMP-8 levels (p < 0.05). Moreover, melatonin supplementation resulted in a more significant decrease in bleeding and pocket depth scores at probing, especially at 3 months (p < 0.05). Furthermore, RANKL and MMP-8 levels were significantly lower at 3 months and IL-1β levels at 6 months compared to the control group (p < 0.05). However, OPG levels were not affected significantly by the treatments (p > 0.05). CONCLUSION: Melatonin, as a host modulation agent, significantly increases the clinical efficacy of fmSRP. The reduction in periodontal inflammation and pocket depths may be a result of marked suppression of RANKL-associated osteoclastogenesis and extracellular matrix damage by melatonin.