Herein, for the first time, we demonstrate that the combination of copper-cysteamine (Cu-Cy) nanoparticles (NPs) and potassium iodide (KI) can significantly inactivate both Gram-positive MRSA and Gram-negative E. coli. To uncover the mystery of the killing, the interaction of KI with Cu-Cy NPs was investigated systematically and the products from their interaction were identified. No copper ions were released after adding KI to Cu-Cy NPs in cell-free medium and, therefore, it is reasonable to conclude that the Fenton reaction induced by copper ions is not responsible for the bacterial killing. Based on the observations, we propose that the major killing mechanism involves the generation of toxic species, such as hydrogen peroxide, triiodide ions, iodide ions, singlet oxygen, and iodine molecules. Overall, the powerful combination of Cu-Cy NPs and KI has good potential as an independent treatment or a complementary antibiotic treatment to infectious diseases.