Advanced glycation end products (AGEs)-evoked response is an important event in colon tumorigenesis. The aim of this study was to investigate the effect of flavonoid derivatives isolated from breadfruit Artocarpus communis on AGEs-enhanced colon malignancy in vitro. According to results, glyceraldehyde-derived AGEs (AGE; 200 μg/mL) enhanced the malignancy of HCT116 colon cancer cells; however, treatment with flavonoid derivatives (2′,4,4′,-trihydroxy-3′-[6-hydroxy-3,7-dimethyl-2(E),7-octadienyl]chalcone, AC-a; 6-geranyl-4′,7-dihydroxyflavanone, AC-b; 5′-geranyl-2′,4,4′-trihydroxydihydrochalcone, AC-c; 6-geranyl-4 ,5,7-trihydroxyflavanone, AC-d) inhibited these changes. These flavonoid derivative-induced biological actions are associated with the modulation of MAPK/NF-κB cascades and translocation of STAT3 and β-catenin. Furthermore, we first found that proliferation of HCT116 cells increased when cultured in conditioned media from AGE-induced THP-1 monocytes (AGE-CM), which may be closely related to the action of AGE-stimulated pro-carcinogenic factors in monocytes; however, flavonoid derivatives retarded aforementioned AGE-CM-evoked phenomena. In conclusion, our study first demonstrates that flavonoid derivatives show great potential in ameliorating AGE-enhanced colon malignancy.