Silver nanoclusters capped with bovine serum albumin (AgNC@BSA) were synthesized and applied for the electrocatalytic reduction of CO2 . Inspired by the fact that many enzymes function only in the presence of coenzymes/cofactors that transfer electrons/protons or other groups, an electron transfer mediator was introduced to facilitate the electrical communication between the electrode and the strongly protected catalyst. The AgNC@BSA catalyst mediated by [α-SiW12 O40](4-) anions showed high electrocatalytic activity for CO2 reduction, which was not observed with either component on its own, in dimethylformamide containing 1 % (v/v) water. CO was the major product with excellent faradaic efficiency (>75 %). The onset potential for this catalytic CO2 reduction process is about 400 mV more positive than that found at a bulk silver electrode. This mediator-enhanced catalysis concept provides a general approach to investigate the electrocatalytic activities of nanoclusters, which remain largely unexplored.