Hepatic encephalopathy (HE), sarcopenia, and frailty are serious complications of chronic liver disease that may negatively affect quality of life and survival. HE is a complex neuropsychiatric multifactorial syndrome for which ammonia is believed to play a key role. Sarcopenia, which is nearly universal in chronic liver disease, is a muscle disease characterized by low muscle strength, low muscle quantity or quality, and low physical performance. Physical frailty is described as a multidimensional syndrome of decreased reserve, functional impairment, and resistance to stressors, resulting from cumulative declines across multiple systems, whereas cognitive frailty is characterized by reduced neurophysiological reserve. Pathophysiology of sarcopenia and frailty in the setting of HE and chronic liver disease remains to be elucidated. Therapeutic strategies of HE aim at reducing blood ammonia concentrations. In that context, muscle may play a vital compensatory role in reducing ammonia levels since it contains an ammonia-removing enzyme. Assessing HE, sarcopenia, and frailty during chronic liver disease is the cornerstone of optimal intervention.