Mercury is considered a risk factor for the development of hypertension and other cardiovascular diseases. Heavy metal mercury chloride (HgCl2) is poisonous and has been linked to significant liver and kidney damage in both humans and animals. Melatonin (MEL) has been discovered to have strong antioxidant qualities that may reduce HgCl2-induced oxidative stress and related tissue damage. This investigation aims to find out whether MEL may have protective effects on HgCl2-induced oxidative stress, malondialdehyde (MDA) generation, kidney, liver, heart, thyroid gland, and brain histopathological changes in rats. The experimental animals were divided at random into three groups. Group 1 (control), Group 2 (HgCl2 treated), and Group 3 (HgCl2 + MEL treated) for 28 days, and ALP, ALT, and AST were examined as liver function test indicators. Serum MDA levels in HgCl2-treated rats were considerably (P0.05) higher than in the control group. While MEL administration for 5 weeks significantly reduced it when compared to HgCl2-treated rats. The kidney, liver, heart, thyroid gland, and brain sections from the control group exhibited a normal arrangement. Conversely, rats treated with HgCl2 displayed distinct histopathological changes in these tissues. Intriguingly, these histopathological degenerative changes didn’t appear in the HgCl2 and MEL-treated group. Conclusion: This study demonstrated that HgCl2 exposure induces oxidative stress, leading to organ damage and histopathological changes in rats. Melatonin supplementation showed promise in decreasing oxidative stress-induced damage by removing free radicals, enhancing antioxidant enzymes, and decreasing MDA levels. While MEL exhibited potential protective effects in mitigating inflammatory responses, edema, and degeneration in various organs, further research is needed to fully understand its mechanisms and optimize treatment strategies for combating mercury-induced toxicity.