Background Two main aims of this animal study were to inspect the possible effects of periodontitis on the structure and functions of the kidneys and the therapeutic effectiveness of melatonin. Methods Twenty‐four male Sprague‐Dawley rats were randomly divided into three groups: control, experimental periodontitis (Ep), and Ep‐melatonin (Ep‐Mel). Periodontitis was induced by placing 3.0‐silk sutures sub‐paramarginally around the cervix of right‐left mandibular first molars and maintaining the sutures for 5 weeks. Then melatonin (10 mg/kg body weight/day, 14 days), and the vehicle was administered intraperitonally. Mandibular and kidney tissue samples were obtained following the euthanasia. Periodontal bone loss was measured via histological and microcomputed tomographic slices. On right kidney histopathological and immunohistochemical, and on the left kidney biochemical (malonyl‐aldehyde [MDA], glutathione, oxidative stress [OSI], tumor necrosis factor [TNF]‐α, interleukin [IL]‐1β, matrix metalloproteinase [MMP]‐8, MMP‐9, and cathepsin D levels) evaluations were performed. Renal functional status was analyzed by levels of serum creatinine, urea, cystatin‐C, and urea creatinine. Results Melatonin significantly restricted ligature‐induced periodontal bone loss (P <0 .01) and suppressed the levels of proinflammatory cytokines (TNF‐α and IL‐1β), oxidative stress (MDA and OSI), and proteases (MMP‐8, MMP‐9, and CtD) that was significantly higher in the kidneys of the rats with periodontitis (P <0.05). In addition, periodontitis‐related histological damages and apoptotic activity were also significantly lower in the Ep‐Mel group (P <0.05). However, the markers of renal function of the Ep group were detected slightly impaired in comparison with the control group (P >0.05); and the therapeutic activity of melatonin was limited (P >0.05). Conclusion Melatonin restricts the periodontitis‐induced inflammatory stress, apoptosis, and structural but not functional impairments.