It was aimed to investigate the biochemical and histopathological effects of resveratrol and melatonin, via histone H4 and β-defensin 1, in diabetic rats. Twenty-four Sprague-Dawley male rats were categorized into 4 groups, with 6 rats in each group (control, diabetes mellitus, melatonin - diabetes mellitus, and resveratrol+diabetes mellitus). Diabetes was formed by giving streptozotocin to all groups except the control group. Melatonin, 5 mg/kg/day, was given to the melatonin - diabetes mellitus group, and resveratrol, 5 mg/kg/day, was given to the resveratrol+diabetes mellitus group via intraperitoneally for 3 weeks. Interleukin-1 beta, tumor necrosis factor alpha, histone H4, and β-defensin 1 levels were measured in the blood of all rats. The lung, liver, and kidney tissue of all rats were performed as histopathological examinations. Whereas there was no difference between the other groups (P >.05), interleukin-1 beta levels of the diabetes mellitus group were found to be significantly higher compared with the control group (5.02 ± 2.15 vs. 2.38 ± 0.72 ng/mL; P < .05). Whereas histone H4 levels of the diabetes mellitus group were higher compared with the control and resveratrol+diabetes mellitus groups (7.53 ± 3.30 vs. 2.97 ± 1.57 and 3.06 ± 1.57 ng/mL; P <.05), the β-defensin 1 levels of the diabetes mellitus group were lower compared with control and resveratrol+diabetes mellitus groups (7.6 ± 2.8 vs. 21.6 ± 5.5 and 18.8 ± 7.4 ng/mL; P <.05). β-Defensin 1 levels were moderately inversely correlated with interleukin-1 beta and histone H4 levels (rs > -0.50, P < .01). Histopathological changes found in favor of target cell damage in the diabetes mellitus group were not observed in resveratrol+diabetes mellitus group. Resveratrol may be used as a biotherapeutic agent, which significantly reduces diabetes-induced histone H4 and interleukin-1 beta-mediated liver and other target organ damage.