Cerebral ischemic injury, one of the leading causes of morbidity and mortality worldwide,
triggers various central nervous system (CNS) diseases, including acute ischemic stroke (AIS) and
chronic ischemia-induced Alzheimer's disease (AD). Currently, targeted therapies are urgently needed
to address neurological disorders caused by cerebral ischemia/reperfusion injury (CI/RI), and the
emergence of neutrophil extracellular traps (NETs) may be able to relieve the pressure. Neutrophils
are precursors to brain injury following ischemic stroke and exert complicated functions. NETs extra-
cellularly release reticular complexes of neutrophils, i.e., double-stranded DNA (dsDNA), histones,
and granulins. Paradoxically, NETs play a dual role, friend and foe, under different conditions, for ex-
ample, physiological circumstances, infection, neurodegeneration, and ischemia/reperfusion. Increas-
ing evidence indicates that NETs exert anti-inflammatory effects by degrading cytokines and chemo-
kines through protease at a relatively stable and moderate level under physiological conditions, while
excessive amounts of NETs release (NETosis) irritated by CI/RI exacerbate the inflammatory response
and aggravate thrombosis, disrupt the blood-brain barrier (BBB), and initiates sequential neuron injury and tissue damage. This review provides a comprehensive overview of the machinery of NETs formation and the role of an abnormal cascade of NETs in CI/RI, as well as other ischemia-induced neurological diseases. Herein, we highlight the potential of NETs as a therapeutic target against ischemic stroke that may inspire translational research and innovative clinical approaches.