Green synthesis offers a sustainable and biocompatible alternative to conventional chemical methods for Cerium oxide nanoparticle (CNPs) synthesis. It minimizes toxic waste and environmental hazards while improving functional performance. Chemical routes often require high temperatures, strong reducing agents and toxic solvents whereas green synthesis yields nanoparticles with smaller sizes, controlled morphologies, and bioactive surface coatings derived from polyphenols, sugars, and proteins. Phytochemicals including polyphenols, sugars, and proteins not only facilitate cerium oxide nanoparticle nucleation but also promote oxygen vacancy formation and modulate the Ce3+/Ce4+ redox coupling, which is a key to the catalytic, antioxidant, and free radical-scavenging activities of CNPs. Recent advances have shifted to green CeO₂ synthesis toward a phytochemical-directed defect engineering approach, allowing precise tuning of surface chemistry, redox states, and oxygen vacancy density through plant-derived ligands and optimized synthesis conditions. Green synthesized CNPs shows enhanced colloidal stability, improved biocompatibility, and reduced cytotoxicity due to the presence of biogenic capping layers. These features expand through the applications in catalysis, environmental remediation, biosensing, drug delivery, radioprotection, and biomedical imaging. Emerging applications include sonocatalytic wastewater treatment, ultrasensitive biosensors for food safety detection, and chitosan-CNPs nanocomposites for accelerated wound healing. Despite these promising advances, challenges related to reproducibility, size uniformity, purification and regulatory approval remain critical barriers for large-scale biomedical and industrial applications. Presently, this review focuses majorly on green routes of Cerium oxide nanoparticles synthesis and its relevant biological applications. Additionally, it discusses their physicochemical and toxicological evaluations, and life cycle assessment to ensure safe and scalable translation. Clinical Trial Number Declaration- Not Applicable.
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