This is a double-blind, placebo-controlled, parallel-grouped clinical trial, which was designed to investigate the potential effects of melatonin add-on treatment with lithium and risperidone on acute manic episodes in patients with bipolar disorder (BD). A total of 54 patients were included and randomly assigned into two groups of melatonin and placebo. The trial group received 3 mg/day risperidone, 900 mg/day lithium, and 6 mg/day melatonin. The placebo group received the same dose of risperidone and lithium plus placebo. The participants were evaluated at four sessions, consisting of baseline, weeks 1, 4, and 6. The manic symptoms and overall clinical improvement of the patients were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I), respectively. Two trial groups were matched based on all baseline characteristics. The patients in two trial groups had comparable serum lithium levels at weeks 1, 4, and 6. Our results from the general linear model repeated measures analysis showed a significant effect for time × treatment interaction on YMRS scores (P = 0.021 and F-value = 3.7). Furthermore, outcomes of the CGI-I rating scale demonstrated that patients in the melatonin group had better clinical improvements compared to the placebo group (P = 0.018). Our results provided preliminary evidence supporting melatonin as an effective adjunctive treatment leading to significant improvements in manic symptoms and overall clinical status in acute episodes of mania.