An orthogonal and regioselective synthesis of triazole disulfides in aqueous media under mild conditions has been developed. This simple and practical approach is environment-friendly and compatible with oxygen/water and various complex biological media. It features excellent regioselectivities and chemoselectivities, high yields, good biocompatibility and bioorthogonality. Its applications in the synthesis of carbohydrates and trigger-responsive nanoparticles are further highlights of this aqueous transformation.