Background: Acute respiratory distress syndrome (ARDS) patients with COVID-19 require sedation or neuromuscular blocking agents to facilitate mechanical ventilation. Aim: to assess the effect of two management protocols on the clinical outcomes of ARDS patients with COVID-19. Research design: This randomized controlled trial included 80 patients with COVID-19 admitted in intensive care units of main hospital Assiut University in Egypt. Sample: A purposive sample was collected according to inclusion criteria. Tools: four tools were included in this study. Methods: ICU nurses and the researchers evaluated the clinical outcomes of administer sedatives versus muscle relaxant protocols among ARDS patients with COVID-19. Propanol and midazolam were used in the – sedatives protocol, and cisatracurium was used in the muscle relaxant protocol. The clinical outcome measures were oxygenation parameters, lung mechanics, tissue perfusion parameters, organ failure, success of weaning, and survival in 28 days. Results: More than two-thirds (67.5 %) of the sedation group were successfully weaned from mechanical ventilation from the first trial, while more than half (57.5 %) of the muscle relaxant group needed another trial for weaning, with a statistically significant difference between both groups. The mean duration of mechanical ventilation was not significantly between the muscle relaxant group (9.24± 5.66) and the sedation group (8.27 ± 3.91). Conclusion: Severe ARDS patients with COVID-19 who underwent the sedation protocol were successfully weaned from mechanical ventilation from the first attempt, compared to those who used muscle relaxants. Morality rate was significantly reduced by sedation compared to using muscle relaxant.