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.