Zearalenone (ZEN) is a thermostable, lipophilic, non-steroidal estrogenic mycotoxin produced by Fusarium spp. that persistently contaminates cereals and feed, posing major risks to food safety, human and animal health, and environmental sustainability. Conventional physical and chemical detoxification methods often compromise nutritional quality and leave toxic residues. This review critically evaluates recent advances in ZEN degradation, integrating physical, chemical, biological, and emerging hybrid approaches, and compares their mechanistic efficiency and applicability. Biological systems employing microorganisms and recombinant enzymes such as peroxidases, laccases, and lactonases exhibit high substrate specificity and eco-compatibility, yet remain limited by enzyme stability and cofactor dependence. Innovative methods including cold atmospheric plasma, polyphenol-mediated redox systems, and nanobiotechnology enhance degradation via reactive species generation, electron transfer, or catalytic surface interactions. Conceptually, this review synthesizes cross-disciplinary progress linking enzymatic catalysis with nanomaterial-assisted detoxification, highlighting hybrid enzyme-nanoparticle systems and synthetic-biology-driven enzyme engineering as promising solutions. Persistent gaps include industrial scalability and regulatory acceptance. Future research should emphasize integrated multi-modal frameworks that couple enzymatic precision with nanomaterial reactivity to achieve efficient, residue-free, and sustainable ZEN detoxification.