This study investigated the antimetastatic activity of four Hericium erinaceus edible mushroom extracts using CT-26 murine colon carcinoma cells as an indicator of inhibition of cell migration to the lung. Hot water (HWE) and microwaved 50% ethanol (MWE) extracts of H. erinaceus strongly elicited cancer cell death through apoptosis and inhibited metastasis of cancer cells to the lungs by 66% and 69%, respectively. HWE and MWE reduced the expression of matrix metalloproteinases MMP-2 and MMP-9 in cells and their activities in culture media. Urokinase-type plasminogen activator (u-PA), another extracellular matrix (ECM)-degrading proteinase, also showed decreased protein expression. In CT-26 cells, HWE and MWE down-regulated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylations. The reduced phosphorylations seem to cause reduction of activity of the MMPs, thereby blocking migration and invasion of cells. Dietary administration of HWE and MWE reduced the formation of tumor nodules in the lung by about 50% and 55%, respectively, and prevented increases in lung weight caused by cancer cell metastasis. These results demonstrate the effectiveness of HWE and MWE as beneficial antimetastatic agents, targeting their upstream signaling molecules for mediating the expression of the ECM-degrading proteinases. Acidic and alkaline extracts were not bioactive. Bioactivity seems to be related to composition. H. erinaceus edible mushrooms have the potential to serve as a health-promoting functional food.