We present density functional theory calculations on the reaction mechanism of thiophene hydrodesulfurization (HDS) over ReS2 (001) surface under typical HDS reaction conditions. It is found that thiophene adopts an “upright” adsorption configuration with the binding energy of 1.26 eV. Considering the factors such as Bader charge, two reaction mechanisms, named direct desulfurization (DDS) to the product of butadiene and hydrogenation (HYD) to 2-butene, 1-butene, and butane, are systematically investigated. Results show that H prefers to attack thiophenic C before the first C–S bond rupture but begins to hydrogenate ST (S atom of thiophene) after ring-opening. Prehydrogenation has different effect on the activity of C–S bond breaking. When the ring is intact, it has nominal effect; but when the ring is open, appropriate prehydrogenation can dramatically decrease the energy barrier while complete hydrogenation makes the barrier rise again due to stereohindrance effect. The DDS mechanism is proved to be kin...