The high-efficient electrochemical hydrogen evolution reaction (HER) is a promising pathway to provide clean energy. An electrocatalyst was computer-aided designed with Mo isolated single atoms (Mo-ISA) supported on heteroatom S, N-codoped carbon having excellent HER performance. Here, by performing comprehensive density functional theory (DFT) computations, we investigated the influence of the N dopent concentration and the sites of S atom doping on the HER performance. Our computed results demonstrate that the Mo-ISA/N1C and Mo-ISA/S-6 N1C catalysts possess good stability and high HER reactivity. Moreover, the interactions between hydrogen and the Mo atoms could be controlled by the N dopent concentration on carbon support, and the MoISA/N1C catalyst showed best HER reactivity. In particular, the S atom was introduced into Mo-ISA/N1C at the S-6 site showing an enhanced HER performance due to the competitive effect of the S-induced tensile strain and charge transfer. Our DFT computations open up new opportunities for application of S, N-codoped Mo-based high-efficient catalysts for HER.