Governing the fundamental reaction of oxygen and lithium in lithium–oxygen batteries is vital to realizing their potentially high energy density. Here, we report novel oxygen reduction reaction (ORR) catalysts that are capable of mediating the lithium and oxygen reaction within a solution-driven discharge, which promotes the solution-phase formation of lithium peroxide (Li₂O₂), thus enhancing the discharge capacity. The new ORR catalysts are derived from mimicking the biological redox mediation occurring in the respiration system of a bacteria, where biomolecule mediates the oxidation of reduced flavin mononucleotide and the reduction of cytochrome b in the cell membrane. The redox potential of the molecule in the biological environment is demonstrated to coincide with the suitable ORR potential range of lithium–oxygen batteries in aprotic solvent, thereby enabling its successful functioning as a redox mediator (RM) that triggers the solution-based discharge. The use of the catalyst prevents the growth of film-like Li₂O₂ even in an ether-based electrolyte, which has been reported to induce surface-driven discharge and early passivation of the electrode, thus boosting the discharge capacity by ~30 times. The similarity of the redox mediation in the biological cell and lithium–oxygen ‘cell’ inspires the exploration of various redox active bio-organic compounds for potential high-performance RMs toward achieving high theoretical specific energies for lithium–oxygen batteries.