Foxtail millet (Setaria italica) is a globally distributed crop rich in essential nutrients, serving as an important source of food and feed. However, its growth and productivity are increasingly threatened by cadmium (Cd) pollution. In this study, to investigate the physiological and molecular responses of foxtail millet to Cd stress, seedlings were treated with 0, 250 or 500 mu M Cd2(+) for 1, 2 or 3 days. Their morphological, physiological, ultrastructural, and molecular responses were systematically analyzed. The results showed obvious morphological changes, including leaf darkening, reduced vitality, and shoot dwarfing, with more severe effects observed at higher Cd concentrations. Notably, Cd stress led to a significant increase in proline content, relative electrical conductivity, and malondialdehyde levels in both shoots and roots, accompanied by dramatic changes in the activities of antioxidant enzymes including peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT). Ultrastructural analysis further revealed severe cellular damage, characterized by distorted chloroplasts in leaves and shrunken root tips. Transcriptomic profiling identified differentially expressed genes in both shoots and roots, which were significantly enriched in pathways related to oxidative stress response, photosynthesis, and metal ion transport. Additionally, a genome-wide analysis identified eight SiNRAMP genes in foxtail millet, among which SiNRAMP5 and SiNRAMP8 were significantly upregulated in both shoots and roots under Cd exposure. These findings provide new insights into the physiological, ultrastructural, and molecular responses of foxtail millet to Cd stress and underscore the potential roles of SiNRAMP in Cd detoxification and tolerance mechanisms.