<p>Chemical warfare agents (CWAs), including nerve agents, blister agents, choking agents, and blood agents, pose severe threats to human health and environmental security due to their neurotoxic, immunosuppressive, and oxidative stress-inducing properties. Although conventional antidotes, including atropine, pralidoxime, and various oximes and chelators, have proven effective, they are often associated with significant toxicity, limited availability, and high costs. These limitations necessitate the development of alternative, sustainable countermeasures. Phytochemicals, a diverse group of plant-derived bioactive compounds—including alkaloids, polyphenols, flavonoids, and terpenoids—are emerging as promising natural defenses against CWAs. Their multifaceted biological activities, such as antioxidative, anti-inflammatory, metal-chelating, immune-modulating, and tissue-regenerative properties, offer an eco-friendly and effective alternative countermeasure against CWAs. This review comprehensively explores the potential of phytochemical-based antidotes as a revolutionary natural shield against CWAs. Among phytochemicals, flavonoids and polyphenols play pivotal roles in detoxification mechanisms by upregulating antioxidant enzymes, including Glutathione S-Transferase (GST), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and Superoxide Dismutase (SOD), while simultaneously suppressing pro-inflammatory pathways. Notably, phytochemicals such as quercetin, resveratrol, curcumin, and silymarin not only contribute to detoxification but also enhance adaptive immune responses by promoting T-cell and B-cell activation, thereby offering a multifaceted defense strategy against CWA-induced toxicity. Terpenoids, including ginsenosides, geniposides, and andrographolide, bolster hepatoprotective and neuroprotective mechanisms through the activation of phase I/II detoxification enzymes and neutralization of reactive oxygen species (ROS). Similarly, alkaloids such as galantamine and berberine activate the Nrf2/ARE signaling pathway, strengthening cellular defense mechanisms and offering protection against oxidative and inflammatory damage caused by CWAs. Furthermore, phytochemicals exhibit strong metal-chelating properties, mitigating neurotoxicity and multi-organ damage linked to toxic metals present in CWAs. Their ability to counteract nerve agent toxicity through acetylcholinesterase (AChE) modulation, suppression of neuroinflammation, and enhancement of neuronal survival further highlights their therapeutic potential. Recent advances in nanophytochemistry have significantly improved the bioavailability, targeted delivery, and controlled release of these bioactive compounds, optimizing their efficacy in CWAs defense. Moreover, the integration of phytochemicals into functional textiles, protective formulations, and nutraceutical-based countermeasures represents a paradigm shift in biodefense strategies. By bridging phytochemistry with pharmacology and nanotechnology, this review underscores the transformative potential of plant-derived compounds in chemical warfare preparedness, presenting a sustainable, globally accessible, and biocompatible strategy for mitigating the toxicological impact of CWAs.</p> Graphical abstract <p></p>