Taken together, our findings demonstrate that the ERK pathway plays a critical role in the synergistic enhancement of the anticancer effects of cetuximab combined with cisplatin on colon cancer cell growth via suppression of the expression of p-EGFR along with the inhibition of COX-2, IL-8, and AP-1 and NF-κB. Here, CXCL8 is linked to malignant colon neoplasm.