The nitric oxide (NO) pathway and its physiological significance on relaxing smooth muscle and endothelial cells throughout the body is well outlined and understood. Components of this pathway have been located in the ocular anterior and posterior chambers, and they have been connected with vascular, retinal, and trabecular meshwork normal physiology. Nitric oxide has been shown to increase anterior chamber aqueous outflow via reduction in trabeculocyte size and smooth muscle contractility, and Schlemm's canal vasodilation. Anti-vascular endothelial growth factor (VEGF) therapy has been shown to disrupt the normal nitric oxide signaling pathway, producing systemic arterial hypertension following systemically administered anti-VEGF in oncology by exactly that mechanism. Intravitreal anti-VEGF therapy is now considered a standard of care in several retinal diseases. Sustained elevated intraocular pressure (IOP) has been described as a potential adverse effect of therapy that appears related to the number of injections, and it can be produced by any of the various anti-VEGF compounds. We propose a novel mechanism responsible for the increase in IOPs following prolonged intravitreal anti-VEGF therapy. This mechanism postulates a rise in IOP due to a decrease in aqueous outflow from relatively decreased levels of available nitric oxide in the anterior chamber because of anti-VEGF inhibition of nitric oxide synthase. This article outlines the novel mechanism, which provides a likely explanation for this consequence, along with offering therapeutic targets for future research and treatment.