Two-dimensional (2D) vertical heterojunctions possess peculiar electronic and optoelectronic properties according to their complementary composition, ultrathin thickness, and unique geometry. However, it is still a challenge to synthesize 2D vertical heterojunctions based on non-layered materials due to strong covalent bonds and abundant surface dangling bonds. Here we developed a partial cation exchange method for the synthesis of 2D vertical Cu₂S/CdS heterojunctions. Large-size and single-crystalline CdS nanosheets prepared by a van der Waals epitaxy method served as host lattices for cation exchange reactions. The evolution of the nanosheets in terms of their morphology, composition and crystal structure was elaborately characterized. The as-prepared 2D vertical heterojunctions have two-layer ultra-thin structures and form large-area junctions at their interfaces. Under light irradiation, the photogenerated electron–hole pairs can be quickly separated under the electric field in the junction region, minimizing the possibility of charge recombination. As a result, the device based on 2D vertical Cu₂S/CdS heterojunctions exhibits a higher photoelectric conversion capability compared with the device based on single-component 2D CdS or Cu₂S Schottky junctions. Our work opens up opportunities to explore 2D vertical heterojunctions based on non-layered materials for high-performance optoelectronic devices.