The design of efficient and cost-effective platinum-based catalysts for the hydrogen evolution reaction (HER) is critical for energy sustainability. Herein, we report high catalytic activity toward HER on the edges of platinum nanoclusters (NCs) supported on single-layer molybdenum disulfide and provide a direct link between ab initio calculations and electrochemical experiments. We determine the active catalytic sites using a cluster expansion method in conjunction with an ab initio thermodynamic approach and show that the system is thermodynamically active at HER reversible potential under electrochemical conditions. We also show that the preferred HER mechanism is the Volmer–Tafel pathway with the Volmer reaction as the rate-determining step. Using a Butler–Volmer kinetic model to simulate a linear sweep voltammogram, we obtain an exchange current density of 10–3–10–2 A/cm2, which is in the same order as those measured for Pt(111) and supported Pt NCs. Importantly, we show that, contrary to expectation...