Inspired by the cubic Mn4CaO5 cluster of natural oxygen‐evolving complex in Photosystem II, tetrametallic molecular water oxidation catalysts, especially M4O4 cubane‐like clusters (M=transition metals), have aroused great interest in developing highly active and robust catalysts for water oxidation. Among these M4O4 clusters, however, copper‐based molecular catalysts are poorly understood. Now, bio‐inspired Cu4O4 cubanes are presented as effective molecular catalysts for electrocatalytic water oxidation in aqueous solution (pH 12). The exceptional catalytic activity is manifested with a turnover frequency (TOF) of 267 s−1 for (LGly‐Cu)4 at 1.70 V and 105 s−1 for (LGlu‐Cu)4 at 1.56 V. Electrochemical and spectroscopic study revealed a successive two‐electron transfer process in the Cu4O4 cubanes to form high‐valent CuIII and CuIIIO. intermediates during the catalysis. Cu4O4 cubanes show exceptional activity for electrocatalytic water oxidation in aqueous solution, with a turnover frequency of 267 s−1 for (LGly‐Cu)4 at 1.70 V and 105 s−1 for (LGlu‐Cu)4 at 1.56 V, respectively. The unique cuboidal structure and high catalytic performance is reminiscent of the natural Mn4CaO5 clusters in PS II.