<p>Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood–brain barrier (BBB)—the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood—also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB–dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.</p>