Coronavirus disease 2019 (COVID-19) affected millions of people worldwide. The pandemic had a significant impact on critical care and in particular on sedation management. Esketamine has emerged as an essential component of the analgesia and sedation regimen for both noninvasively and invasively ventilated patients. It has numerous beneficial effects, including hemodynamic stabilization, reduction of opioid requirements, neuroprotection, and anti-inflammatory effects. This article discusses the use of esketamine in the intensive care of patients with COVID-19 but also reflects on the benefits and promising perspectives for all critically ill patients. Ketamine is consistently listed as an essential drug by the World Health Organization. In a conversation with an experienced intensivist, the practical use of esketamine, its benefits, adverse effects, and differentiated use in a well-defined sedation management strategy for everyday care and perspectives for emerging new indications will be presented.