Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome induced by liver disease. HE is characterized by cognitive and motor disturbances, along with sleep disturbances, that progress and expands and finally altered mental status is obvious, leading to coma and death. Three types of HE have been defined: (1) Type A HE, associated with acute liver failure; (2) Type B HE, associated with portal-systemic shunting in the absence of liver disease or failure and (3) Type C HE, associated with chronic liver disease from different etiologies as alcohol consume, chronic hepatitis, or obesity. Different animal models have been developed to study the pathological mechanisms of HE. These models should reproduce etiopathology and HE symptoms observed in humans, but it results difficult due in part to the complex and variable etiopathology and multiple factors modifying disease progression, including presence of different complications after liver disease affecting different organs. In addition, it is yet difficult to reproduce in animals some features of mental alterations present in humans. In spite of this, the studies in animal models have allowed to known basic and common mechanisms of HE, mainly related to hyperammonemia and inflammation, and to propose several therapeutic targets. The efficacy of pharmacological modulation of these mechanism-based therapeutic targets has also been evaluated in these different preclinical animal models of HE. In this chapter, we describe the most used animal models of Type A and Type C HE.