Aim To investigate the effects of systemically administered melatonin on inflammation and alveolar bone resorption in rats with experimentally induced periapical lesions. Methodology Thirty adult Sprague Dawley rats were divided equally into negative, positive control and melatonin groups. The pulp chambers of their mandibular first molars were exposed to the oral environment to induce experimental periapical lesions in the positive control and melatonin groups. The melatonin group received daily intraperitoneal injections of melatonin at a dose of 10 mg kg(-1). After 21 days, the animals were euthanized; the hemi-mandible parts were prepared for radiological, histopathological, immunohistochemical (IL-1 beta, RANK, RANKL, OPG and tartrate-resistant acid phosphatase (TRAP) and Brown-Brenn (bacteria) evaluations. Data were analysed by Kruskal-Wallis (for non-parametric data) and one-way anova tests (for parametric data) (P < 0.05). Results The area of radiographic periapical bone loss was significantly smaller in rats that were given daily intraperitoneal injections of melatonin (P < 0.01). The histopathological scores of the melatonin group were significantly lower than those of positive control group (P < 0.01). Histomorphometrically, the area of periapical bone loss in the melatonin group was significantly smaller than the positive control group (P < 0.01). The expression of IL1-beta, RANK and RANKL was significantly higher in the positive control group, whereas OPG was significantly higher in the melatonin group (P < 0.01). The number of osteoclasts was significantly greater in the positive control group by TRAP staining analyses (P < 0.01). The scores for bacteria localization using Brown-Brenn staining in the melatonin group was significantly lower than that of the positive control group (P < 0.01). Conclusions Melatonin demonstrated antiresorptive effects on bone associated with experimentally induced periapical lesions in rats via its anti-inflammatory activity. Further studies are necessary to evaluate its possible effects on the healing of periapical lesions.