In the present study, we for the first time demonstrated that enalapril, a clinically widely used antihypertensive drug, significantly enhanced the efficacy of 5-FU in suppressing tumor growth and metastasis in CRC without additional toxicity through inhibition of proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins, showing an attractive therapeutic strategy for CRC. Here, NFKB1 is linked to colorectal carcinoma.