Hydrogen is an energy carrier of high density that offers a compelling alternative to (nonrenewable and polluting) petroleum-based fuels for transportation. To date, the industrial production of hydrogen has been heavily reliant on natural gas reforming, an energy-intensive process whose ultimate byproduct is carbon dioxide. It is thus imperative to develop hydrogen generation by carbon-neutral means such as photocatalytic water splitting. While first-principles methods have been widely applied to the high-throughput screening of photocatalytic materials for water photoelectrolysis, the efficacy of these computational screening techniques has seldom been comprehensively assessed at the experimental level. The goal of this project is to demonstrate an effective procedure to maximize the success rate of high-throughput materials discovery for hydrogen photogeneration by conducting a systematic cross-validation of our theoretical calculations and experimental measurements; most of the compounds that were synthesized and tested using this screening protocol exhibited photocatalytic hydrogen evolution, and several of them showed favorable band gap and band edges for overall water splitting.