The design and synthesis of electrocatalysts with controllable active sites are highly desirable for producing hydrogen. Inspired by the experimental realization of two-dimensional metal-organic framework (2D-MOF) nanosheets, a computational screening was performed to find out the optimal single-atom catalysts for the hydrogen evolution reaction (HER) from 36 2D-MOFs composed of transition metal and benzene-like molecular ligands. Through first-principles calculations, six configurations were identified as potential catalysts for the HER with performance comparable to those of Pt-based catalysts due to the near-zero Gibbs free energy and favourable activation barriers originating from their appropriate d-orbital bonding mechanism with atomic hydrogen.