Herein, we investigate thiol-based catalysis using maleic acid as the substrate and simple thiols having key functional groups as molecular catalysts in neutral aqueous solutions (Fig. ). We found that aqueous radical activation, rather than ionic processes, is crucial for the molecule-based isomerization of maleate to fumarate to be catalytic, where the thiol unit would be converted into a thiyl radical via 1e -/1H + activation (nominal hydrogen atom transfer, HAT, from thiols). A "chemical mutational study" showed the importance of thiol and intramolecularly adjacent groups for efficient catalysis, and L-cysteine (1) was found to be one of the most efficient molecular catalysts in the reaction in the presence of otherwise less reactive radical initiators. The mechanistic understanding of the aqueous thiyl radical-catalyzed chemical reaction was corroborated by computational chemistry. The catalysis eventually exceeded 2,500 cycles under the optimized conditions, showcasing superior performance compared to conventional catalytic systems. Furthermore, the scalability of this catalytic process for large-scale synthesis using thiyl radicals showed an advantage over conventional catalytic systems, demonstrating the potential of the catalysis using aqueous thiyl radicals.