Zinc oxide nanoparticles (ZnO NPs), an attractive oxide semiconductor material, are widely used in the biomedical field due to their good biosafety and economy. The proposal of stimuli-responsive materials provides a new way for the further application of single ZnO-based nanomaterials that cannot meet the ever-changing requirements. In this review, the emerging advances in exogenous stimuli (light, ultrasound, mechanical force, etc.) and endogenous stimuli (pH, enzymes, etc.) responsive systems of ZnO-based nanomaterials in biomedical applications are highlighted. First, the basic characteristics, response mechanisms and construction principles of single-stimulus-responsive ZnO-based nanomaterials, as well as their recent advances in tissue repair, medical devices and theranostics are summarized. Subsequently, the design method of multi-stimuli-responsive ZnO-based biomaterials is discussed, and the application advantages of multi-functional responsive systems are explained by analyzing typical cases of biomedical applications of multi-responsive strategies. Finally, we discuss the prospects for the design and development of stimuli-responsive ZnO-based biomaterials for biomedical applications and point out their advantages as well as the places that need to be further improved. The current review may provide a useful reference for researchers interested in constructing such abundant, inexpensive and widely applicable multi-stimuli-responsive materials.