The objective of the current study was to develop an optimized formulation for orally disintegrating tablets (ODTs) containing melatonin. Different particle sizes of mannitol (i.e., filler) were used to study the effects on dissolution and tablet properties using a quality by design (QbD) approach. The quality target product profile was identified, then critical quality attributes (CQAs) were determined. Risk assessment was performed using the Failure Mode Effect Analysis (FMEA) method to identify and rank critical material attributes and process parameters. Thirty-four formulations were prepared and tested. Box-Behnken design (BBD) with response surface methodology was applied to assess the effect of independent factors on CQAs. Finally, the most suitable formulation in terms of tablet properties was determined with Minitab. Specification tests were applied to confirm that the optimized formula met USP requirements. Mannitol with a small particle size had the fastest disintegration time and dissolution rate in ODT formulations containing melatonin.