PURPOSE: Melatonin is a natural hormone that regulates circadian rhythms. The aim of this study was to compare the anxiolytic effects of oral melatonin and oral midazolam in patients undergoing third molar surgery. The study also sought to investigate the effects of these drugs on cognitive and psychomotor functions. MATERIALS AND METHODS: This was a double-blinded, prospective, randomized clinical study. Patients scheduled for impacted third molar surgery were included in the study. Anxiety was evaluated with the visual analog scale (VAS). To measure psychomotor and cognitive functions before the procedure, all patients were asked to complete the digit symbol substitution test (DSST) and the trail making test (TMT parts A and B). Then, all patients were allocated to 1 of 3 groups to receive oral midazolam 0.2 mg/kg (group MD), oral melatonin 0.4 mg/kg (group M), or an oral multivitamin tablet as placebo (group P). After 60 minutes, patients were reassessed using the same 3 tests. The difference between the pre- and post-drug VAS values was calculated and the anxiolytic effects of the drugs were evaluated. RESULTS: Ninety patients participated in the study. No relevant differences were observed among groups for age, gender, or duration of operation. The results suggested that anxiety decreased most in group MD (P < .001), but anxiety in group M also decreased significantly compared with group P (P = .016). Similarly, the greatest increase in TMT-A and -B score differences was in group MD compared with the other groups (P < .001), whereas there was no significant difference between groups M and P for TMT-A and -B scores (P = .913 and P = .964, respectively). CONCLUSION: Melatonin showed sufficient anxiolytic effect in third molar surgery without affecting cognitive and psychomotor functions.