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Lettuce is one of the most famous leafy vegetables worldwide with lots of applications from food to other specific uses. There are different types in the lettuce group for consumers to choose from. Additionally, lettuce is an excellent source of bioactive compounds such as polyphenols, carotenoids, and chlorophyll with related health benefits. At the same time, nutrient composition and antioxidant compounds are different between lettuce varieties, especially for green and red lettuce types. The benefit of lettuce consumption depends on its composition, particularly antioxidants, which can function as nutrients. The health benefits rely on their biochemical effect when reaching the bloodstream. Some components can be released from the food matrix and altered in the digestive system. Indeed, the bioaccessibility of lettuce is measuring the quantity of these compounds released from the food matrix during digestion, which is important for health-promoting features. Extraction of bioactive compounds is one of the new trends observed in lettuce and is necessarily used for several application fields. Therefore, this review aims to demonstrate the nutritional value of lettuce and its pharmacological properties. Due to their bioaccessibility and bioavailability, the consumer will be able to comprehensively understand choosing a healthier lettuce diet. The common utilization pattern of lettuce extracted nutrients will also be summarized for further direction.