This study aimed to select a combination of curcumin and luteolin, two phytochemicals from food, at lower concentrations with a higher inhibitory effect on colon cancer growth and investigate possible molecular mechanisms of this anti-colon cancer effect. By pairwise combination screening, we identified that the combination of curcumin (CUR) at 15 μM and luteolin (LUT) at 30 μM (C15L30) synergistically suppressed the proliferation of human colon cancer CL-188 cells, but the individual chemicals had a little inhibitory effect at the selected concentrations. This result was also confirmed in other colon cancer DLD-1cells, suggesting that this synergistic inhibitory effect of C15L30 applies to different colon cancer cells. The combination C15L30 synergistically suppressed the wound closure (wound healing assay) in CL-188 cells. We also found that the combination of CUR and LUT (at 20 mg/kg/day and 10 mg/kg/day, respectively, IP injection, 5 days for 2 weeks) synergistically suppressed tumor growth in CL-188 cell-derived xenograft mice. Western blot results showed that protein levels of Notch1 and TGF-β were synergistically reduced by the combination, both in CL-188 cells and xenograft tumors. Tumor pathological analysis revealed that combined CUR and LUT synergistically increased necrosis, but the individual treatment with CUR and LUT had no significant effect on tumor necrosis. Therefore, combined curcumin and luteolin synergically inhibit colon cancer development by suppressing cell proliferation, necrosis, and migration associated with Notch1 and TGF-β pathways. This study provides evidence that colon cancer may be prevented/treated by consuming foods having high levels of luteolin and curcumin in humans