Melatonin is a pineal gland neuro-hormone influencing the biological regulations of the circadian rhythm. Numerous investigations have revealed variable effects of melatonin in vivo, including anti-inflammatory, antioxidant, sedative, and anxiolytic effects. The effects of using exogenous melatonin as an adjuvant to propofol on the degree of sedation in patients were investigated. We aimed to test the feasibility of melatonin as a sedative agent in traumatic brain injury patients. This research was a double-blinded clinical trial conducted on 38 participants suffering from traumatic brain injuries necessitating sedation and mechanical ventilation. Participants were assigned randomly into two groups. Both groups were sedated by propofol infusion and monitored by bispectral index (BIS). Nineteen patients received 10 mg of melatonin, and 19 patients received a placebo (control). Propofol infusion rate and BIS values were recorded each 30 minutes for 12 hours. Exogenous melatonin administration led to a significant decrease in the amount of infused propofol necessary to attain the desired level of sedation. The propofol infusion rates were 4.87 ± 2.91 ml/h in the melatonin group and 6.37 ± 2.87 ml/h in the control group (P- values = 0.001). Exogenous melatonin acts as an adjuvant to propofol in sedation, reducing the amount of propofol infusion needed.