Amorphous MoS3 (a-MoS3) is an appealing low-cost catalyst for the hydrogen evolution reaction (HER), which is a promising process for electrocatalytic hydrogen generation. In this study, we scrutinize the stability and HER catalytic activity of carbon-supported Mo3S9–x-clusters under electrochemical conditions by using grand-canonical density functional theory (GC-DFT) coupled with a cluster-continuum solvation strategy. We show that some sulfur atoms of the Mo3S9 cluster can be removed as H2S under HER conditions. This partial desulfurization leads to a stable working state of Mo3S8 or Mo3S7 with HER catalytic activity at moderate thermodynamic overpotentials. The desulfurization process simultaneously induces water adsorption on undercoordinated molybdenum sites. The so-formed hydrated Mo3S9–x-clusters can exhibit two distinct active sites. On Mo3S8(H2O)2, the top SH* species are active for the HER, whereas OH* species are involved in the HER on Mo3S7(H2O)3. By comparison with a previous study of the HER catalyzed by 2H–MoS2 edge sites, we demonstrate that S-defective a-MoS3 is an efficient HER electrocatalyst. Moreover, in contrast to active sites on 2H–MoS2, the HER mechanism on Mo3S9–x-clusters involves a protonation step instead of the common proton-coupled electron transfer, an elementary reaction step that required GC-DFT to be identified.