Critical illness is characterized by substantial hormone- and cytokine-mediated protein metabolism changes in various organs, leading to increased breakdown and decreased synthesis rates. Consequently, a considerable and life-threatening loss of muscle mass occurs. Medical therapeutic measures such as long-term sedation and mechanical ventilation during ICU stay can further enhance this muscle degradation (up to 2 % muscle mass per day leading to clinically relevant symptoms known as ICU-acquired weakness, a clinical symptom that is classified as a secondary disorder. If left unabated, these circumstances might strongly affect long-term patient outcomes. This study consists of 20 mechanically ventilated patients expected to stay in the intensive care unit (ICU) for at least 4 days. We used indirect calorimetry to determine energy expenditure and guide caloric provision to the patients randomized to the high protein and early exercise (HPE) group and the control group. Protein intakes were 1.48 g/kg/day and 1.19 g/kg/day medians respectively; while the former was submitted to two daily sessions of exercise, the latter received routine physiotherapy. We evaluated the primary outcome physical component summary (PCS) score at 3 and 6 months and the secondary outcomes (handgrip strength at ICU discharge and ICU and hospital mortality. In this prospective randomized controlled trial, we found that a high protein intake and resistance training led to an improvement in the physical quality of life of critically ill patients as measured by the PCS score after 3 and 6 months. We also found a reduction in mortality rate and a tendency to improvement in the ICU-acquired weakness measured through handgrip strength in the study group.