Over-the-counter (OTC) analgesics are among the most widely prescribed and purchased drugs around the world. Most analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are metabolized in the liver. The hepatocytes are responsible for drug metabolism and detoxification. Cytochrome P450 enzymes are phase I enzymes expressed mainly in hepatocytes and they account for approximate to 75% of the metabolism of clinically used drugs and other xenobiotics. These metabolic reactions eliminate potentially toxic compounds but, paradoxically, also result in the generation of toxic or carcinogenic metabolites. Cumulative or overdoses of OTC analgesic drugs can induce acute liver failure (ALF) either directly or indirectly after their biotransformation. ALF is the result of massive death of hepatocytes induced by oxidative stress. There is an increased interest in the use of natural dietary products as nutritional supplements and/or medications to prevent or cure many diseases. The therapeutic activity of natural products may be associated with their antioxidant capacity, although additional mechanisms may also play a role (e.g., anti-inflammatory actions). Dietary antioxidants such as flavonoids, betalains and carotenoids play a preventive role against OTC analgesics-induced ALF. In this review, we will summarize the pathobiology of OTC analgesic-induced ALF and the use of natural pigments in its prevention and therapy.