Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of acute and chronic liver dysfunction, and is characterized by a spectrum that ranges from mild neuropsychological disturbances to coma. Although ammonia plays a critical role in the pathogenesis of HE, the plasma concentrations of ammonia and manifest symptoms of HE are not always consistent in patients with HE. Recently, a substantial body of evidence has indicated that inflammation acts in concert with ammonia in the pathogenesis of HE. Meanwhile, emerging novel and potential therapeutic strategies, including N-acetylcysteine, hypothermia, minocycline, non-steroidal anti-inflammatory drugs, tumour necrosis factor-alpha antagonists and p38 inhibitors, have been reported to ameliorate systemic inflammation and neuroinflammation, improve or reverse neuropsychiatric manifestations, and prevent the onset and progression of HE in patients and/or animal models of acute or chronic liver failure. These results point to the possible therapeutic utility of decreasing inflammation in the treatment of HE, and translation of these experimental results to the clinic may provide novel and promising therapeutic approaches for patients with HE secondary to acute or chronic liver failure. This review will provide an overview of these potential targeted therapies in the prophylaxis and treatment of HE.