This article describes the synthesis and antioxidative properties of melatonin derivatives. Tryptamines and cysteinyl or mercaptopropionyl derivatives were deliberately condensed with coupling reagents to give melatonin derivatives 4a–d and 5a, b. The preliminary evaluation indicated that compound 4c showed improved scavenging activity compared with vitamin C (IC50 43 μm vs 65 μm, where IC50 is the concentration of the test compound that induced a change of 50% in absorbance during the 30 min observation) on diphenyl-p-picrylhydrazyl (DPPH) tests. Derivative 5b, which possesses the thiolactyl moiety, showed moderate potency compared with melatonin (IC50 235 μm vs 690 μm) in the H2O2 scavenging test. Intriguingly, 4c displayed 2-fold more potency than melatonin (IC50 51 μm vs 125 μm) in scavenging NO in the macrophage model. These results suggested that the cysteinyl-conjugated derivative 4c may be a suitable lead to further optimize potent antioxidants for certain oxidative stress conditions.