The purpose of this study was to evaluate the anticancer efficacy of cetuximab combined with cisplatin (combination treatment) on colon cancer growth, as well as its underlying action mechanism. Combination treatment synergistically potentiated the effect of cetuximab on cell growth inhibition and apoptosis induction in HCT116 and SW480 cells. Combination treatment further suppressed the expression of the activated form of epidermal growth factor receptor (EGFR) and MAP kinase (p-ERK and p-p38) and also significantly inhibited the activity of activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). Additionally, the expression of cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA was significantly reduced by the combination treatment as compared to the expression seen for treatment with cetuximab or cisplatin alone. We found that the synergistic inhibitory effects of cetuximab and cisplatin on AP-1 and NF-κB activation, as well as on cell viability, were reversed by pretreatment with an ERK inhibitor. Results demonstrate that combined treatment with cetuximab and cisplatin exerts synergistic anticancer effects on colon cancer cells and also suggest that the ERK pathway plays a critical role in these effects via the suppression of the EGFR signaling pathway, along with the inhibition of COX-2, IL-8, and AP-1 and NF-κB.