The use of ketamine for procedural sedation and analgesia outside the operating room (OR) in different settings, such as during electroconvulsive therapy, endoscopy, bronchoscopy, magnetic resonance imaging, pediatric dentistry, dressing of burn patients, and trauma patients in pre-hospital settings, offers unique advantages of preservation of spontaneous breathing, airway reflexes, and hemodynamic stability with excellent analgesia. However, isolated ketamine often leads to undesired emergence reactions, nausea, vomiting, and hemodynamic stimulation, causing a search for effective and safe drug combinations to enhance the efficacy of sedation and analgesia regimen while mitigating adverse effects of single drugs under careful monitoring. This chapter addresses the evidence-based utility of ketamine and esketamine and effective, safe drug combinations for sedation and analgesia in different non-OR settings to enhance patient comfort and procedural efficiency.