Background: Luteolin, a natural flavonoid, exerts anticancer activities. In this study, we evaluated the role of luteolin in colon cancer, and its underlying mechanisms. Materials and Methods: The effect of luteolin on the proliferation of human colon tumor (HCT)-116, SW480, and Caco-2 cells was evaluated. Subsequently, the effect of luteolin on the proliferation, migration, and invasion of HCT-116 cells was monitored. Then, we analyzed the level of inflammation and oxidative stress in the mouse model transplanted with HCT-116 under in situ conditions. Furthermore, we investigated whether luteolin attenuates growth of colon tumor under in vivo conditions. Results: Our results demonstrate that luteolin reduced the proliferation of HCT-116, SW480, and Caco-2 cells. In addition, it blocked the migration and invasion of HCT-116 cells. Moreover, luteolin increased the production of interleukin (IL)-2/10 and decreased the production of IL-6, interferon-β, tumor necrosis factor-α, and IL-1 β. Furthermore, it increased the level of superoxidase dismutase and glutathione peroxidase and decreased the levels of malondialdehyde significantly. Luteolin significantly lowered the sensitization of NOD-leucine-rich repeat and pyrin-containing protein 3 (NLRP3)/caspase-1/IL-1 β signal axis. Luteolin exerted the above actions in a dose-dependent manner. Conclusion: The results of this study indicate that luteolin mitigates the growth of colon cancer via suppressing the inflammatory processes, oxidative stress, and NLRP3/IL-1 β signal axis. It might serve as a promising candidate for colon cancer.