As the bottleneck in photocatalytic water splitting, the oxygen evolution reaction (OER) has drawn huge attention, but its efficiency still falls short of expectations. A widely accepted speculation is that the catalysts’ activity is insufficient (high reaction barriers need to be overcome). Here, we develop a first-principles method to investigate the photocatalytic OER at the water/TiO2(110) interface. A full mechanism uncovering the importance of radicals is determined. Kinetic analysis further enables to quantitatively estimate each possible obstacle in the process. We demonstrate unambiguously that the rate-determining factor of the OER varies with the concentration of surface-reaching photoholes (Ch+). Under experimental conditions, the intrinsic catalytic activity of TiO2(110) does not represent the main obstacle, but all steps involving the photoholes are slow due to their low concentrations. This suggests that the key to enhance the OER efficiency is to increase Ch+ before Ch+ reaches the estimated threshold (Ch+ = ~10−4).