Antioxidant treatments have been expected to be a novel therapeutics for various oxidative stress-mediated disorders. Our previous study revealed that 5-hydroxyoxindole and its 3-phenacyl-3-hydroxy derivatives showed excellent antioxidant activities such as 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and lipid-peroxidation inhibitory activity. However, the DPPH radical scavenging activity of the 3,3-disubstituted derivatives was lower than that of the original 5-hydroxyoxindole. In the present study, we synthesized novel 3-monosubstituted 5-hydroxyoxindole derivatives that exhibited stronger DPPH radical scavenging activities and lipid peroxidation-inhibitory activities than the 3,3-disubstituted 5-hydroxyoxindoles. Moreover, the 3-monosubstituted 5-hydroxyoxindole derivatives showed neither an iron-mediated pro-oxidant effect nor a remarkable cytotoxicity against HL-60 cell lines except some of the highly lipophilic compounds. These results indicate that 3-monosubstituted 5-hydroxyoxindoles can be used as a promising antioxidant scaffold for drug discovery.