Zearalenone (ZEN) is a toxic secondary metabolite mainly produced by fungi of the genus Fusarium, and is often present in various food and feed ingredients such as corn and wheat. The structure of ZEN is similar to that of natural estrogen, and it can bind to estrogen receptors and has estrogenic activity. Therefore, it can cause endocrine-disrupting effects and promote the proliferation of estrogen receptor-positive cell lines. In addition, ZEN can cause oxidative damage, endoplasmic reticulum stress, apoptosis, and other hazards, resulting in systemic toxic effects, including reproductive toxicity, hepatotoxicity, and immunotoxicity. In the past few decades, researchers have tried many ways to remove ZEN from food and feed, but it is still a challenge to eliminate it. In recent years, natural compounds have become of interest for their excellent protective effects on human health from food contaminants. Researchers have discovered that natural compounds often used as dietary supplements can effectively alleviate ZEN-induced systemic toxic effects. Most of the compounds mitigate ZEN-induced toxicity through antioxidant effects. In this article, the contamination of food and feed by ZEN and the various toxic effects and mechanisms of ZEN are reviewed, as well as the mitigation effects of natural compounds on ZEN-induced toxicity.