Chlorogenic acid (CGA) is a naturally occurring non-flavonoid polyphenol found in green coffee beans, teas, certain fruits, and vegetables, that exerts antiviral, antitumor, antibacterial, and antioxidant effects. Several in vivo and in vitro studies have demonstrated that CGA can protect against toxicities induced by chemicals of different classes such as fungal/bacterial toxins, pharmaceuticals, metals, pesticides, etc., by preservation of cell survival via reducing overproduction of nitric oxide and reactive oxygen species and suppressed pro-apoptotic signaling. CGA antioxidant effects mediated through the Nrf2-heme oxygenase-1 signaling pathway were shown to enhance the levels of antioxidant enzymes such as superoxide dismutase, catalase, glutathione-S-transferases, glutathione peroxidase, and glutathione reductase as well as glutathione content. Also, CGA could suppress inflammation via inhibition of toll-like receptor 4 and MyD88, and the phosphorylation of inhibitor of kappa B and p65 subunit of NF-κB, resulting in diminished levels of downstream inflammatory factors including interleukin (IL)-1 β, IL-6, tumor necrosis factor-α, macrophage inflammatory protein 2, cyclooxygenase-2, and prostaglandin E2. Moreover, CGA inhibited apoptosis by reducing Bax, cytochrome C, and caspase 3 and 9 expression while increasing Bcl-2 levels. The present review discusses several mechanisms through which CGA may exert its protective role against such agents. Chemical and natural toxic agents affect human health. Phenolic antioxidant compounds can suppress free radical production and combat these toxins. Chlorogenic acid is a plant polyphenol present in the human diet and exerts strong antioxidant properties that can effectively help in the treatment of various toxicities.