There is a great deal of interest in identifying new chemopreventive agents for colorectal cancer, one of the leading causes of cancer-related death. One promising group of candidates is the polyphenols; being natural compounds with high structural diversity, they have a very wide spectrum of anti-inflammatory, anti-oxidant and anti-cancer properties. The present study reports for the first time that spent hops extract (SHE) inhibits the angiogenesis, invasion and migration of SW-480 and HT-29 colorectal adenocarcinoma cells; after incubation with 200 μg/mL SHE, SW-480 and HT-29 cell invasion fell by 98.5% and 89% vs. controls, and migration was inhibited by 99% and 88% vs. controls. These changes were accompanied by a decline of matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and activity. In addition, SHE reduced the expression of vascular endothelial growth factor and hypoxia-inducible factor 1α for both cell lines, indicating that the tested extract has anti-angiogenic potential. In conclusion, our data shows that SHE may be an effective chemopreventive agent acting via the inhibition of angiogenesis, invasion and migration of colorectal cancer cells.