AbstractWe report a straightforward design for a hybrid glucose biofuel cell (h‐GBFC) operating at pH 7.4 with 10 mM glucose at 37 °C. Homemade electrospun carbon nanofibers were used as electrode support. Clean and highly active gold‐based nanomaterials (3–6 nm) were synthesized for glucose electrooxidation. Enhanced catalytic activity toward glucose oxidation has been highlighted. Bilirubin oxidase enzyme was used to catalyze the oxygen reduction reaction. The constructed h‐GBFCs exhibit an unexpected and highly improved open circuit voltage of 0.92 V, which is the best value so far reported for such cells. The abiotic Au60Pt20Pd20/C anode induces high electrical performance with a maximum power density of 91 µW cm−2 at 0.365 V. This improvement over monometallic anode catalysts has been assigned to synergistic effects between gold, platinum, and palladium. Strategies developed herein will serve as guidelines for the development of new rational pathways to more powerful, stable, and promising GBFC designs.