Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.