Aim: To evaluate the effect of melatonin on C-reactive protein, serum ferritin and D–dimer level in adult patients with severe coronavirus disease 2019 (COVID-19). Method: This single center, prospective, randomized clinical trial conducted in Al-Shifaa hospital at Mosul, Iraq from 1st December 2020 to 1st June 2021 on 158 patients divided into two groups 82 patients in melatonin group (given 10 mg melatonin) and 76 patients in control group. Then C-reactive protein (CRP), serum ferritin and D-dimer level were evaluated and recorded at day 5, 11, 17 of symptoms. Results: Totally, 82 patients in the intervention group and 76 patients in the control group have completed the treatment. In comparison with the control group, the level of CRP, serum ferritin and D-dimer have significantly improved (P is less than 0.05) in melatonin group in the second week of infection. Conclusions: The adjuvant use of melatonin in COVID-19 patients has a potential to improve CRP, ferritin, and D-dimer.