Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are natural compounds that have been found in various foods and plants. These compounds have attracted much attention in recent years due to their potential health benefits, including their ability to protect against natural and chemical toxins. This article comprehensively reviews the promising effects of caffeic acid and CAPE against natural and chemical toxins. Mechanisms supporting the protective effects of these compounds, such as antioxidant, anti-inflammatory, and anti-apoptotic properties, are discussed. Studies have shown that caffeic acid and CAPE can protect against a wide range of toxins, including mycotoxins, heavy metals, and environmental toxins. These compounds have also been shown to protect against chemical toxins such as pesticides, industrial chemicals, and pharmaceuticals. Overall, the promising effects of caffeic acid and CAPE against natural and chemical toxins make them potential candidates for developing novel therapeutics and functional foods.