The cerebrovascular endothelium has been reconceptualized from a mere passive barrier to an active regulator of neuroimmune responses. The interaction between immune cells and endothelial cells, particularly at the blood-brain barrier, is pivotal in the context of neuroinflammation and vascular dysfunction associated with various neurological disorders. This comprehensive review synthesizes recent advancements in the molecular and cellular mechanisms that govern this interaction. We investigate how activated endothelial cells interact with immune cells through adhesion pathways, cytokine networks, and metabolic cross-talk, thereby contributing to the pathogenesis of disease. Special attention is given to the influence of vascular aging in exacerbating this dysregulation. Additionally, we assess the translational implications of our findings, including the identification of novel biomarkers, advancements in neuroimaging techniques, and therapeutic strategies aimed at restoring barrier integrity and modulating neuroimmune responses. A comprehensive understanding of the immune-endothelial axis provides a crucial framework for elucidating neurovascular pathophysiology and informing targeted interventions.