Natural plant-derived phenolic extract recently received much attention in the food industry to obtain bioactive compounds for food and pharmaceutical industries. These compounds are of considerable interest due to their medicinal and nutrition properties. In this line, cactus pear (Opuntia spp.) is considered for its potentially active nutrients and its multifunctional properties to produce health-promoting food supplements. These beneficial effects are related to its potential bioactive compounds like phenolic acids and flavonoids possessing antioxidant traits. As secondary metabolites, phenolic compounds can mitigate oxidative damage caused by cancer, cardiovascular diseases, and diabetes. The phenolic structure contains an aromatic ring with one or more hydroxyl groups that cause their therapeutic activity. Two classes of phenolic compounds are extensively investigated in the plants, including hydroxybenzoic acid and hydroxycinnamic acid. However, phenylpropanoid serves as a precursor for synthesizing the other phenolic compounds. Several phenolic compounds were found to display different health benefits, including antioxidant, anti-inflammatory, and anticancer activities. Phenolic acids and flavonoids from the genus Opuntia have been recognized as antioxidants. Phenolic acids such as vanillic, ferulic, p-coumaric, p-hydroxybenzoic, syringic, protocatechuic, caffeic, salicylic, gallic, and sinapic, as well as flavonoids such as rutin, isoquercitrin, kaempferol, and narcissi are found in plants from the genus Opuntia. The antioxidant properties of phenolic compounds in Opuntia spp. plants make them an essential product for preventing human health against degenerative diseases such as cancer, diabetes, hypercholesterolemia, arteriosclerosis, cardiovascular and gastric diseases. Nowadays, the food and agricultural processing include phenolic compounds as an essential part of the human diet. This chapter discusses the medicinal importance of phenolic compounds in Opuntia spp. as a natural antioxidant. The article highlights the extractions methods and manufacturing processing, including backing, cooking, and frying, in the food and beverage industry and their effects on these compounds’ stability and activity. This information would help identify Opuntia species rich in phenolics and their therapeutic properties. Besides, the chemical structure, properties, and health benefits of phenolic compounds of cactus pear fruit and their influences in agro-industrial wastes as natural sources of antioxidants with application in food industries have been reviewed.