Many strategies to optimize molybdenum selenide based electrocatalysts for hydrogen evolution reaction (HER) have been explored; however, the modulation of molybdenum selenide on the molecular scale remains an ongoing challenge. Here, we synthesized a new molecular HER electrocatalyst based on a molybdenum-selenium cluster (Mo3Se13) and further realized its modulation by precise sulfur substitution at the molecular level to enhance the HER activity. The density functional theory (DFT) calculations demonstrated that the substituted sulfur could promote the hydrogen adsorption process and thus improve the HER performance. This work not only realizes the selective replacement of the bridging selenium atom with a sulfur atom in the molybdenum-selenium cluster for the first time but also provides a precise model for illustrating the structure-property relationship in electrocatalysis on the molecular level.