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Colorectal cancer (CRC) is a major global cause of death, with metastases and chemotherapy resistance contributing to poor outcomes. To identify natural compounds with anticancer potential against CRC and elucidate their action mechanisms, the cytotoxicity of 37 natural compounds was evaluated against the HCT116, leading to the identification of conferone as the lead candidate. Its anti-migratory and anti-invasive effects were evaluated in HCT116, Colo205, and SW480 cells. The interactions between conferone and focal adhesion kinase (FAK) were assessed through protein expression analysis and molecular docking. Glutaminolysis regulation was determined by LC-MS/MS, and related enzyme levels were detected by western blotting. Conferone inhibited migration and invasion in all three CRC cell lines, though it showed limited anti-proliferative activity. At 10 μM, conferone reduced FAK and p-FAK (Tyr397) protein levels, reversing the epithelial-mesenchymal transition. Docking analysis confirmed direct FAK binding and predicted inhibition of its phosphorylation, with greater affinity than the FAK inhibitor 1,2,4,5-benzene tetramine tetrahydrochloride. Conferone also downregulated glutaminase and glutamate-ammonia ligase, increasing glutamine and decreasing glutamic acid. Additionally, it suppressed c-raf phosphorylation and reduced c-Myc expression, blocking glutaminolysis-driven metabolism. These findings highlight conferone as a potential therapeutic agent that targets FAK, alters metabolic reprogramming, and impedes CRC progression.