The incidence and mortality rates of colorectal cancer (CRC) are alarmingly high and the scientific community is consistently engaged in developing newer therapeutic options for cancer cure or prevention. The fluoropyrimidine drug 5-fluorouracil (5FU) remains the first line of treatment against CRC; nevertheless, relapses frequently occur since the cells gain resistance over time through various mechanisms. Studies have highlighted the significance of combinatorial treatment of a Wnt signaling inhibitor and 5FU as a better treatment strategy to overcome 5FU resistance. Small molecules that specifically target and disrupt β-catenin-TCF interaction, a crucial step of the Wnt signaling, are promising in CRC treatment. In this study, we have investigated the synergistic activity of the phytochemicals, plumbagin or menadione, with 5FU as they have previously been shown to downregulate Wnt signaling in CRC cells. Docking results showed that the drug combinations bound to key protein-protein interaction sites of the β-catenin-TCF complex. The drug combinations exerted synergistic cytotoxic effects in CRC cells and the 5FU-menadione combination also downregulated the expression of Wnt signaling proteins. Taken together, our data suggests that the simultaneous binding of 5FU and plumbagin/menadione to β-catenin can block Wnt signaling by disrupting β-catenin-TCF interaction and inhibit the proliferation of CRC cells.