Functionalized ZnO-based nanocomposites have gained significant attention for their diverse biomedical applications. This review discusses current trends and future perspectives in the synthesis and functionalization of ZnO nanoparticles for biomedical uses. ZnO nanoparticles are versatile due to their unique physicochemical properties, including high chemical stability, wide bandgap, and biocompatibility. They are used in biosensing, bioimaging, drug delivery, tissue engineering, and immunotherapy. The review highlights various synthetic approaches, including chemical, green, and biosynthesis methods, which are crucial for producing functionalized ZnO nanoparticles with desired properties. The review also addresses the toxicity mechanisms of ZnO nanoparticles, emphasizing their neurotoxic potential and primary toxicity pathways. The synthesis methods discussed include mechanochemical, hydrothermal, sol-gel, emulsion/microemulsion, controlled precipitation, and green/biosynthesis approaches. Each method has its advantages and challenges, such as cost, scalability, and environmental impact. The review also explores the applications of ZnO nanoparticles in biomedical fields, including their use in drug delivery, antimicrobial applications, and tissue regeneration. The study emphasizes the importance of controlling the size, shape, and structure of ZnO nanoparticles to optimize their performance in biomedical applications. The review concludes with a discussion on the future directions of ZnO-based nanocomposites in biomedicine, highlighting the need for further research to enhance their functionality and safety.Functionalized ZnO-based nanocomposites have gained significant attention for their diverse biomedical applications. This review discusses current trends and future perspectives in the synthesis and functionalization of ZnO nanoparticles for biomedical uses. ZnO nanoparticles are versatile due to their unique physicochemical properties, including high chemical stability, wide bandgap, and biocompatibility. They are used in biosensing, bioimaging, drug delivery, tissue engineering, and immunotherapy. The review highlights various synthetic approaches, including chemical, green, and biosynthesis methods, which are crucial for producing functionalized ZnO nanoparticles with desired properties. The review also addresses the toxicity mechanisms of ZnO nanoparticles, emphasizing their neurotoxic potential and primary toxicity pathways. The synthesis methods discussed include mechanochemical, hydrothermal, sol-gel, emulsion/microemulsion, controlled precipitation, and green/biosynthesis approaches. Each method has its advantages and challenges, such as cost, scalability, and environmental impact. The review also explores the applications of ZnO nanoparticles in biomedical fields, including their use in drug delivery, antimicrobial applications, and tissue regeneration. The study emphasizes the importance of controlling the size, shape, and structure of ZnO nanoparticles to optimize their performance in biomedical applications. The review concludes with a discussion on the future directions of ZnO-based nanocomposites in biomedicine, highlighting the need for further research to enhance their functionality and safety.