In colitis-associated colorectal cancer (CAC), the NF-κB pathway, especially IKKβ, drives inflammation and cancer progression. However, no IKKβ inhibitors have been approved due to compensatory mechanisms. The challenge is to develop an anti-tumor agent that effectively targets IKKβ while overcoming these compensatory pathways. We conducted in vitro and in vivo experiments to evaluate the anti-cancer effects of synthesized xanthohumol (XN) targeting IKKβ. CAC was induced in mice, followed by XN treatment. Histological and molecular analyses, including cell viability assays, immunoblotting, and qRT-PCR, were performed. Human colon cancer cell lines were also used to investigate IKKβ’s role. RNA sequencing revealed elevated IKKβ expression in colorectal cancer human tissues, correlating with poor prognosis. XN significantly reduced adenocarcinoma formation and inflammation in vivo while decreasing IKKβ and NF-κB signaling in both models. XN binds to the C179 residue of IKKβ, inhibiting its activity. Additionally, our findings highlight KEAP1's role as an upstream regulator of IKKβ degradation. XN specifically interacts with the C288 residue of KEAP1, showing triple-binding affinity with IKKβ and KEAP1. These results indicate that XN promotes conditions where KEAP1 facilitates IKKβ degradation.