Melatonin-loaded liposomes (MLL) were successfully prepared using rapid expansion of supercritical solution technology. The effects of supercritical pressure on encapsulation efficiency (EE) and average particle size were then analysed. Meanwhile, temperature, formation time and ethanol concentration in the products were studied and optimised based on the response surface methodology (RSM). An in vitro simulated digestion model was also established to evaluate the release performance of MLL. The results showed that 140 bar was the best pressure for maximising the EE value using RSM optimisation, reaching up to 82.2%. MLL characterisations were performed using analytic techniques including infrared spectroscopy, transmission electron microscopy, a laser scattering particle size analyser and gas chromatograph-mass spectrometer. The size distribution was uniform, with an average diameter of 66 nm. Stability tests proved that MLL maintained good preservation duration, and residual solvent experiments indicated that only 1.03% (mass ratio) of ethanol remained in the products. Simulated release experiments indicated the slow release feature in early digestive stages and more thorough characteristics in later stages of simulated digestion.