Introduction: Hepatic encephalopathy (HE) is a complicated brain disorder that is resulted from the liver failure. In HE, due to the inability of the liver in detoxification, the concentration of toxins, such as ammonia, will be increased in the blood and brain. To preserve neurons from the adverse effects of ammonia, as trocytes convert it to glutamine. The increase in glutamine, in turn, alter osmotic pressure and the volume of the inters titial fluid in the brain. On the other hand, the increase in ammonia level also excites immune cells in the brain and induces neuroinflammation. The high levels of ammonia and subsequent neuroinflammation alter neurotransmitter levels, which in turn induce cognitive dysfunctions, including learning and memory impairments as well as locomotion and coordination disorders. Glutamate and GABA and the downs tream signaling cascades are the main molecular pathways that are affected in HE. Conclusion: According to the lates t molecular data, it can be concluded that different signaling molecules downs tream to the neurotransmitters receptors, such as Ca2+-dependent kinases including protein kinase C and calcium/calmodulin-dependent protein kinase II, mitogen-activated protein kinases and inflammatory cytokines, are proposed as the effective molecules in pathogenesis as well as potential targets for controlling and treatments of HE in the future. Considering the multidimensional appearance of HE, it can be proposed that a complex of treatment s trategies, including the use of lowering ammonia level agents, effective antibiotics, anti-inflammatory drugs, and a balance in protein intake can effectively control the symptoms of HE.