Water splitting using renewable electricity provides a promising way for large-scale hydrogen production due to its zero-carbon emission properties. However, the development of highly efficient, low-cost and durable electrocatalysts remains an ongoing challenge in industrial applications. Herein, a strategy integrating vacancy engineering and metal doping was proposed to design and screen M@CuS catalysts with excellent catalytic activity via density functional theory (DFT) calculations. TM single atoms anchored by the vacancy of the CuS surface show high stability, and serve as the active centers for water splitting. Ti@CuS and Co@CuS exhibit exceptional performance towards the hydrogen evolution reaction (HER). Ti@CuS and Co@CuS can achieve hydrogen adsorption free energies (ΔG_H*) of 0.01 eV and −0.03 eV, respectively. The HER process of Ti@CuS is controlled by the Heyrovsky mechanism. Co@CuS also shows superior catalytic activity towards the oxygen evolution reaction (OER), and presents a relatively lower OER overpotential of 0.41 V. Co@CuS serves as a promising candidate of bifunctional HER/OER electrocatalysts. This work not only provides highly efficient electrocatalysts for water splitting, but also inspires a novel concept to guide the extending design of catalysts in other catalysis fields.