Background: Malnutrition is an important prognostic factor which can influence clinical outcome of patients suffering from chronic liver disease (CLD). Believed to cause hypermetabolism, malnutrition exacerbates hepatic encephalopathy and sarcopenia in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid isoleucine (ILE) and exercise (EX) could possibly attenuate muscle mass loss and prevent brain edema in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + ILE; 3) BDL + EX; 4) BDL + ILE + EX; 5) Sham-operated rats. Two weeks post BDL, BDL + EX rats were submitted to 15 min exercise (10 cm/s) every other day and BDL rats receiving ILE, were gavaged daily (1.5 mg/kg) for 4 weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass) and cerebral edema (specific gravity method) were measured in all groups. Results: BDL + EX + ILE demonstrated a significant gain in body weight (BDL + ILE + EX: 112.3 g vs BDL: 33.7 g; p < 0.05), an increase in muscle mass (weight/body weight ratio) (BDL + ILE + EX: 0.0056 vs BDL: 0.0047; p < 0.05) and attenuated hypermetabolic status. Brain water content was decreased in BDL + ILE + EX rats compared to BDL animals. Conclusion: Our results demonstrate that EX and supplemental ILE improve body weight, muscle mass, metabolic activity and attenuate cerebral edema. These findings suggest that strategies aiming at muscle mass optimization and improving nutritional status attenuate complications and therefore improve outcome in patients with CLD. EX and ILE supplementation could rapidly be translated into clinical practice.