Mammalian ferritin is predominantly in the cytosol, with a minor portion found in plasma. In most insects, including Drosophila melanogaster, ferritin belongs to the secretory type. The functional role of secretory ferritin in iron homeostasis remains poorly understood in insects as well as in mammalians. Here we used Drosophila to dissect the involvement of ferritin in insect iron metabolism. Midgut-specific knockdown of ferritin resulted in iron accumulation in the gut but systemic iron deficiency (37% control), accompanied by retarded development and reduced survival (3% survival), and was rescued by dietary iron supplementation (50% survival) or exacerbated by iron depletion (0% survival). These results suggest an essential role of ferritin in removing iron from enterocytes across the basolateral membrane. Expression of wild-type ferritin in the midgut, especially in the iron cell region, could significantly rescue ferritin-null mutants (first-instar larvae rescued up to early adults), indicating iron deficiency as the major cause of early death for ferritin flies. In many nonintestinal tissues, tissue-specific ferritin knockdown also caused local iron accumulation (100% increase) and resulted in severe tissue damage, as evidenced by cell loss. Overall, our study demonstrated Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification.