Hepatic encephalopathy is a complication of liver failure characterized by neuropsychiatric dysfunction ranging from disorientation to coma. There is a need for more treatment options and preventive care interventions to reduce the incidence of hepatic encephalopathy and mitigate its socioeconomic impact on families and strain on healthcare resources. Currently, there is no consensus on a single pathophysiological mechanism responsible for the development of this neurocognitive disorder. Ammonia toxicity remains a significant factor, but there is now increased recognition that hyperammonemia acts synergistically with systemic inflammation, oxidative stress, and gut microbiota imbalance in the development of hepatic encephalopathy. This article provides an overview of current and emerging therapies that target these factors in the treatment and management of this condition. Because of its complex pathogenesis, a multipronged approach to treating hepatic encephalopathy may be highly beneficial.