Approximately 90% of cancer-associated deaths result from disseminated tumors, indicating the ineffectiveness of current therapies and the imperative need of antimetastatic drugs. A novel pharmacophore with flavonoid and naphthalimide moieties was constructed by using a fragment-based drug design and a series of eight flavone–naphthalimide–polyamine conjugates were synthesized. In vitro evaluation revealed that compound 6c with a homospermidine motif displayed better cell selectivity between cancerous and normal liver cells than amonafide did. The in vivo assays on two hepatocellular carcinoma (HCC) models verified that 6c potently suppressed pulmonary metastasis with improved organ indexes compared to amonafide. Various experiments showed that 6c as a potential fluorescent chemical probe could target the mitochondria. Preliminary investigation into the mechanism of action of 6c indicated that it might harness a polyamine transporter for cell entrance, localize in the mitochondria, selectively cause reactive oxygen species (ROS) overproduction in hepatoma cells instead of normal liver cells, and finally lead to HCC cell apoptosis and migration inhibition via multiple ROS-mediated signaling pathways.