To prepare a water-soluble catalyst for photocatalytic hydrogen (H2) evolution, a simple hydrophobic precursor of [FeFe]–H2ase mimics, Fe2S2(CO)6, has been successfully assembled on the surface of CdSe QDs using an interface-directed approach in aqueous/organic solution. The resulting photocatalyst shows the highest efficiency known to date for H2 evolution with a turnover number (TON) of 8781 vs. Fe2S2(CO)6 and an initial turnover frequency (TOF) of 596 h−1 under visible light irradiation in water.