Noninvasive ventilation (NIV) is one of the most frequently used artificial respiratory support for acute respiratory failure. The therapy, although noninvasive, has an impact on the patients’ cognitive and affective attitudes, and often, patients feel claustrophobic and short of breath, leading to anxiety. Further, the interface is required to be tightly held on the facial structure, which also contributes to pain and anxiety. All these factors have been implicated in NIV intolerance and failure. While non-pharmacological measures and cause correction should be applied first to address the intolerance, pharmacological sedation is often required. Sedation, on the other hand, is a double-edged sword during NIV. Therefore, the decision to use sedation, especially the choice of drug, and the appropriate timing are critical for better results. Different drugs have different actions on cardiorespiratory functions. Further, the side effect profile of the sedatives in the context of the NIV therapy requisite also needs to be considered. The present chapter briefly describes the relevant pharmacokinetics and evidence of the commonly used sedative drugs.