Lettuce is one of the most commonly consumed leafy vegetables worldwide and is available throughout the entire year. Lettuce is also a significant source of natural phytochemicals. These compounds, including glycosylated flavonoids, phenolic acids, carotenoids, the vitamin B groups, ascorbic acid, tocopherols, and sesquiterpene lactones, are essential nutritional bioactive compounds. This review aims to provide a comprehensive understanding of the composition of health‐promoting compounds in different types of lettuce, the potential health benefits of lettuce in reducing the risks of chronic diseases, and the effect of preharvest and postharvest practices on the biosynthesis and accumulation of health‐promoting compounds in lettuce.