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Exogenous melatonin can be helpful for treatment of some sleep disorders. However, immediate-release formulations are rapidly absorbed and cleared from the body making it difficult to provide coverage for an entire sleep period. Extended-release melatonin formulations can better mimic the naturally occurring melatonin profile and increase efficacy, but few studies have reported on their pharmacokinetics. To assess the pharmacokinetics of extended-release melatonin, we conducted a randomized, double-blind, crossover study of extended-release melatonin (4 mg) compared to immediate-release melatonin (4 mg) in 18 healthy adults, ages 18-65 years. Participants received immediate-release or extended-release melatonin in clinic after an 8 h fast, and blood samples were taken over a 10-h period. After a 7-day washout period, the same procedures were repeated with the melatonin form not previously received. Extended-release melatonin had a longer time to peak concentration (1.56 vs 0.6 h) and elimination half-life (1.63 vs 0.95 h) compared with immediate-release melatonin. Maximum concentration was lower for extended-release melatonin compared with immediate-release melatonin (7581 pg/mL vs 13120 pg/mL). Extended-release melatonin raised melatonin levels in as little as 15 min and sustained elevated melatonin levels (>300 pg/mL) for 6 h before falling below 50 pg/mL by 9 h. No clinically relevant adverse events were observed, and safety parameters remained within normal ranges for both formulations. The pharmacokinetic profile of this extended-release melatonin formulation suggests that it could be used for future efficacy studies of melatonin and sleep outcomes. This trial is registered at ClinicalTrials.gov, NCT04067791.