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Aqueous electron mediators for point-of-care testing require a variety of properties, such as rapid dissolubility, high stability, and moderate formal potential (near 0 V). Using the redox-active properties of quinone derivatives, various quinone-containing electron mediators have been developed for electrochemical sensors. However, most quinone derivatives exhibit very low solubility in aqueous solutions and instability in the presence of nucleophilic species. Herein, we report a strategic design for quinones incorporating sulfonated thioether and nitrogen-containing heteroarene moieties as solubilizing, stabilizing, and formal potential-modulating groups. Systematic investigations found that di(thioether sulfonate)-substituted quinoline-1,4-dione (QLS) and quinoxaline-1,4-dione (QXS) displayed high water solubility and rapid dissolubility. By finely balancing the electron-donating effect of the thioethers and the electron-withdrawing effect of the nitrogen atom, formal potentials suitable for electrochemical biosensors are achieved with QLS and QXS (−0.15 and −0.09 V vs Ag/AgCl, respectively, at pH 7.4). QLS is stable for >1 d in PBS (pH 7.4) and for 1 h in tris buffer (pH 9.0), which is sufficient for point-of-care testing. Furthermore, QLS, with its high electron mediation ability, is successfully used in biosensors for sensitive detection of glucose and parathyroid hormone. This strategy provides organic electron mediators that exhibit rapid dissolution and high stability and will find broad applications beyond quinone-based biosensors. Figure 1