Infections are a leading cause of morbidity and mortality in patients with acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). CNS injury disrupts the balanced interplay between the immune system and the CNS, leading to secondary immunodepression (CIDS) and increased susceptibility to infection. CIDS results in profound deficiencies of the body's defense systems, leaving the host vulnerable to invading microorganisms. The article reviews clinical and experimental evidence for CIDS after CNS injury, focusing on stroke, TBI, and SCI. It highlights the importance of understanding CIDS to develop effective therapeutic strategies to improve outcomes after CNS damage. The mechanisms by which CNS injury induces immunodepression, including humoral and neurogenic signaling, are discussed, along with the potential therapeutic targets for modulation of CIDS. The authors emphasize the need for further research to elucidate the pathophysiology of CNS-immune interactions and to develop targeted interventions to enhance recovery in patients with CNS injuries.Infections are a leading cause of morbidity and mortality in patients with acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). CNS injury disrupts the balanced interplay between the immune system and the CNS, leading to secondary immunodepression (CIDS) and increased susceptibility to infection. CIDS results in profound deficiencies of the body's defense systems, leaving the host vulnerable to invading microorganisms. The article reviews clinical and experimental evidence for CIDS after CNS injury, focusing on stroke, TBI, and SCI. It highlights the importance of understanding CIDS to develop effective therapeutic strategies to improve outcomes after CNS damage. The mechanisms by which CNS injury induces immunodepression, including humoral and neurogenic signaling, are discussed, along with the potential therapeutic targets for modulation of CIDS. The authors emphasize the need for further research to elucidate the pathophysiology of CNS-immune interactions and to develop targeted interventions to enhance recovery in patients with CNS injuries.