Wastewater management and treatment are crucial to preserve health and life on the planet. To achieve efficient wastewater treatment, MoS 2 nanosheet/ZnS-based composites were prepared and tested for the photodegradation of a model wastewater contaminant, oxytetracycline (OTC), a widely used antibiotic. Various parameters, such as contact time, solution pH, and nanocomposite dosage, were studied to obtain the optimal parameters. Among the various composites, that prepared using 0.25 g of the zinc acetate precursor (denoted MoS 2 /ZnS-0.25) showed the highest photocatalytic activity: 81% OTC degradation in 180 min. The high photocatalytic activity of the nanocomposite can be ascribed to the greater absorption of visible light, enhanced charge carrier transfer, and delayed electron−hole recombination. In addition, first-principles density functional theory calculations were used to understand the mechanism behind the enhanced photocatalytic performance, charge transfer, band alignment, and electronic, optical, and interfacial properties of the MoS 2 nanosheet/ZnS composites. Based on the theoretical calculations, we found that the MoS 2 nanosheet/ZnS composite band structure ensures that electrons are transferred from ZnS to MoS 2 on visible light irradiation. In addition, the potential drop and charge difference at the interface induce a large built-in internal electric field that reduces charge carrier recombination. The results of this study will enable the design of a wider range of two-dimensional van der Waals nanocomposites as photocatalyst materials.