The transcriptional factors nuclear factor-κB (NF-κB) and NF-E2-related factor 2 (Nrf2) have been recently reported to have critical roles in protecting various tissues against inflammation and colitis-associated colorectal cancer (aberrant crypt foci). Our previous studies showed that wogonin (5,7-dihydroxy-8-methoxyflavone) possessed anti-neoplastic and anti-inflammatory activities. The present study extended these important earlier findings by exploring the effect of wogonin on the initiation and development of colitis-associated cancer. Wogonin lowered tumor incidence and inhibited the development of colorectal adenomas in azoxymethane- or dextran sulfate sodium-induced mice. We found that wogonin significantly decreased the secretion and expression of IL-6 and IL-1β, reduced cell proliferation and nuclear expression of NF-κB in adenomas and surrounding tissues and promoted Nrf2 nuclear translocation in surrounding tissues, although overexpressed Nrf2 in tumor tissues was independent of wogonin administration. Furthermore, wogonin inhibited the interaction between human monocytic THP-1 cells and human colon cancer HCT116 cells, and significantly downregulated lipopolysaccharide-induced secretion of prototypical pro-inflammatory cytokines IL-6 and IL-1β in THP-1 cells. Further mechanism research revealed that wogonin inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β, and promoted Nrf2 signaling pathway in HCT116 cells and THP-1 cells. Taken together, the present results indicated that wogonin effectively suppressed inflammation-associated colon carcinogenesis and cancer development, suggesting its potential as a chemopreventive agent against colitis-associated colon cancer.