Chronic exposure to deoxynivalenol (DON)-contaminated food and feed poses significant hepatotoxic, enterotoxic, and immunotoxic risks to humans and animals. Nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial cellular protective factor, plays a pivotal role in oxidative stress, inflammatory responses, and apoptosis. This review demonstrates that modulation of the Nrf2 signaling pathway can mitigate oxidative damage, suppress inflammatory responses and ferroptosis, reduce apoptosis, and alleviate endoplasmic reticulum stress and DON-induced injury, thereby protecting organisms from DON toxicity. Nrf2-targeting agents-including plant extracts, proteins and amino acids, selenium, microbial preparations, and other nutrients-primarily exert protective effects by enhancing Nrf2 expression, promoting its nuclear translocation, and upregulating downstream target genes to counteract DON-induced organotoxicity. Notably, we identified a "threshold effect" of Nrf2 in DON toxicity: moderate oxidative stress activates Nrf2-mediated cytoprotection, whereas excessive oxidative stress suppresses Nrf2 and exacerbates damage. This threshold is a concentration- and context-dependent regulatory boundary jointly determined by DON-induced reactive oxygen species (ROS) burst intensity, Keap1-Nrf2 binding affinity, and downstream pathway integrity. Below the threshold, physiological ROS induces Keap1 conformational change and Nrf2 nuclear translocation; beyond it, excessive ROS impairs Nrf2 activation and triggers its degradation. This review provides novel insights into Nrf2-based therapeutic strategies, offering promising approaches to alleviate DON-induced organ toxicity.