Cerebral ischemic stroke is an acute cerebrovascular disease caused by cerebral vascular occlusion, and it is associated with high incidence, disability, and mortality rates. Studies have found that excessive or insufficient autophagy can lead to cellular damage. Autophagy consists of autophagosome formation and maturation, autophagosome-lysosome fusion, degradation and clearance of autophagic substrates within autolysosomes, and these processes collectively constitute autophagic flux. Research has revealed that cerebral ischemia can induce impaired fusion between autophagosomes and lysosomes, resulting in autophagic flux impairment. Intracellular membrane fusion is mediated by three core components: N-ethylmaleimide sensitive factor (NSF) ATPase, soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs). SNAREs, after mediating fusion between autophagosomes and lysosomes, remain in an inactive complex state on the autolysosomal membrane, requiring NSF reactivation into monomers to perform subsequent rounds of membrane fusion-mediated functions. NSF is the sole ATPase capable of reactivating SNAREs. Recent studies have shown that cerebral ischemia significantly inhibits NSF ATPase activity, reducing its reactivation of SNAREs. This may be a pathological mechanism for impaired fusion between autophagosomes and lysosomes, leading to neuronal autophagic flux impairment. This article discusses the pathological mechanisms of NSF ATPase inactivation, including SNAREs dysregulation, impaired fusion between autophagosomes and lysosomes, and insufficient transport of proteolytic enzymes to lysosomes, and explores approaches to improve neuronal autophagic flux through NSF ATPase reactivation. It provides references for stroke treatment improvement and points out directions for further research.