The inferior electrical properties at the interface of the Cu 2 ZnSnS 4 /CdS (CZTS/CdS) heterojunction resulting in the severe loss of open-circuit voltage (V oc ) highly restrict the photovoltaic efficiency of CZTS solar cell devices. Here, firstprinciples calculations show that the Zn-alloyed CdS buffer layer reverses the unfavorable cliff-like conduction band offset (CBO) of CZTS/CdS to the desirable spike-like CBO of CZTS/Zn 0.25 Cd 0.75 S, which suppresses carrier nonradiative recombination and blocks electron backflow. In addition, the weakened n-type conductivity of Zn 0.25 Cd 0.75 S can be enhanced by In, Ga, and Cl doping without the introduction of detrimental deep-level defects and severe band-tail states, which improves the V oc of CZTS solar cells by promoting strong band bending and large quasi-Fermi-level splitting at the absorber side of the CZTS/Zn 0.25 Cd 0.75 S heterojunction. This study finds that the synergetic effects of Zn alloying and defect engineering on the CdS buffer layer are promising for overcoming the long-standing issue of the V oc deficit in CZTS solar cells, and understanding the optimized interfacial electrical properties provides theoretical guidance for improving the efficiency of semiconductor devices.