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Colorectal cancer (CRC) is one of the major health problems in the Western part of the world, and in India, also CRCs incidence slowly raising due to the unbalanced food habits, especially, high fat diet and low fiber intake. Natural products are safe, and very effective against many cancer types. Luteolin is chemically known as (2-[3, 4-dihydroxyphenyl]-5, 7-dihydroxy-4-chromenone), and it is a flavonoid available as a natural form and it was highly found in certain vegetables and fruits. In this chapter, we have discussed on the anti-tumor effect of Luteolin against CRC. Further, it discusses on how Luteolin modulates the key signalings, such as phosphoinositol-3-Kinase (PI3K)/Akt/Wnt/β-catenin and NF-E2-related factor 2 (Nrf2) pathways. Luteolin may be a strong cytotoxic drug as it facilitates the apoptotic mode of cell death in different cancer models. In a nutshell, the preclinical evidences suggest that Luteolin can be developed as a chemotherapeutic drug that needs to be tested in clinical settings.