<p>The intricate linking between the health of blood vessels and the functioning of neurons has attracted growing attention in the context of disorders that affect the neurological environment. Endothelial cells, forming the blood–brain barrier and blood-retinal barrier, play a fundamental role in maintaining the integrity of the brain-retina microenvironment connection. This review explores the molecular foundations of endothelial cell dysfunction and its implications for the brain-retina interaction. A comprehensive analysis of the complex factors contributing to endothelial dysfunction is presented, including oxidative stress, inflammation, reduced nitric oxide signaling, and disrupted vascular autoregulation. The significance of endothelial dysfunction extends to neurovascular coupling, synaptic plasticity, and trophic support. To our knowledge, there is currently no existing literature review addressing endothelial microvascular dysfunction and its interplay with the brain-retina microenvironment. The review also explains bidirectional communication between the brain and retina, highlighting how compromised endothelial function can disrupt this vital crosstalk and inhibit normal physiological processes. As neurodegenerative diseases frequently exhibit vascular involvement, a deeper comprehension of the interaction between endothelial cells and neural tissue holds promise for innovative therapeutic strategies. By targeting endothelial dysfunction, we may enhance our ability to preserve the intricate dynamics of the brain-retina microenvironment connection and ameliorate the progression of neurological disorders.</p>