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Colorectal cancer (CRC) is one of the most common cancers worldwide. Gut microbiota are highly associated with CRC, and <i>Fusobacterium nucleatum</i> was found to be enriched in CRC lesions and correlated with CRC carcinogenesis and metastases. <i>Paris polyphylla</i> is a well-known herbal medicine that showed anticancer activity. The present study demonstrates that <i>P. polyphylla</i> inhibited the growth of CRC cells. In addition, treating with active compounds pennogenin 3-<i>O</i>-beta-chacotrioside and polyphyllin VI isolated from <i>P. polyphylla</i> inhibited the growth of <i>F. nucleatum</i>. We also found that extracellular vesicles (EVs) released from <i>F. nucleatum</i> could promote mitochondrial fusion and cell invasion in CRC cells, whereas active components from <i>P. polyphylla</i> could dampen such an impact. The data suggest that <i>P. polyphylla</i> and its active ingredients could be further explored as potential candidates for developing complementary chemotherapy for the treatment of CRC.