Infection with carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. In vitro experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.