The universal pollution of diverse water bodies and declined water quality represent very important environmental problems. The development of new and efficient photocatalytic water treatment systems based on the Z-scheme mechanisms can contribute to tackling such problems. This study reports the preparation, full characterization, and detailed sonophotocatalytic activity of a new series of hybrid NU@ZIS nanocomposites, which comprise a p-n heterojunction of 3D Zr(IV) metal-organic framework nanorods (NU-1000) and photoactive ZnIn2S4 (ZIS) nanostars. Among the obtained materials with varying content of ZIS (5, 10, 20, and 30%) on the surface of NU-1000, the NU@ZIS20 nanocomposite revealed an ultrahigh catalytic performance and recyclability in a quick visible-light-induced degradation of the tetracycline antibiotic in water under sonophotocatalytic conditions. Moreover, increased activity of NU@ZIS20 can be ascribed to the formation of a p-n heterojunction between NU-1000 and ZIS, and a synergistic effect of these components, leading to a high level of radical production, facilitating a Z-scheme charge carrier transfer and reducing the recombination of charge carriers. The radical trapping tests revealed that ·OH, ·O2-, and h+ are the major active species in the sonophotocatalytic degradation of tetracycline. Possible mechanism and mineralization pathways were introduced. Cytotoxicity of NU@ZIS20 and aquatic toxicity of water samples after tetracycline degradation were also assessed, showing good biocompatibility of the catalyst and efficacy of sonophotocatalytic protocols to produce water that does not affect the growth of bacteria. Finally, the obtained nanocomposites and developed photocatalytic processes can represent an interesting approach toward diverse environmental applications in water remediation and the elimination of other types of organic pollutants. © 2021 American Chemical Society.