The active compound 4-hydroxybenzaldehyde (4-HBd) has neuroprotective effects, which has been confirmed to have an anti-cerebral ischemia reperfusion injury (CIRI) effect in a previous study. In this study, we explored the protective effect of 4-HBd on the neurovascular unit (NVU) after CIRI and its mechanism through in vivo and in vitro experiments. Using the established rat middle cerebral artery occlusion/reproduction (MCAO/R) model, a transwell chamber was used to establish an in vitro primary simulating pathological CIRI in vivo. The Longa 5-point method was used to evaluate the neurological function of the rats, and transmission electron microscope was used to observe the ultrastructural changes of NVU. Western Blot was used to detect the expression of neuronal proteins in rat brains. The mRNA expressions of the Ang-1/Tie-2 signaling pathway and the BDNF/TrkB signaling pathway were detected by qPCR. In vivo results showed that 4-HBd reduced neurological function scores and improved the ultrastructure of NVU after MCAO/R. 4-HBd could upregulate the expression of microtubule associated protein-2 (Map-2), glial fibrillary acidic protein (GFAP), and occludin. In vitro results showed that 4-HBd could activate the Ang-1/Tie-2 signaling pathway, increased occludin mRNA expression, and protected the blood brain barrier (BBB). 4-HBd can activate the BDNF/TrkB signaling pathway, upregulate Map-2 mRNA expression, and promote neuronal repair. In vitro and in vivo results indicated 4-HBd can affect the Ang-1/Tie-2 and BDNF/ TrkB signaling pathways, BBB damage is alleviated, and NVU homeostasis is maintained to improve CIRI.