: The current systematic review aimed at investigating different medications commonly used for procedural sedation and analgesia (PSA) in emergency departments (EDs) for adults. The articles related to the subject of interest were searched in five electronic databases, including Google Scholar, PubMed, Medline, Web of Science, Scopus, and Embase, up to 2019. The blinded, randomized, controlled, clinical trials comparing common PSA medications, including midazolam, etomidate, propofol, fentanyl, ketamine, and ketofol, among the adults undergoing PSA in EDs were included in the study. The search process resulted in the inclusion of 35 papers in the study. The main information, including clinical features, sedation duration, recovery time, and incidence of adverse events, was extracted from the selected studies. Based on the reviewed studies, various combinations of medications are used for PSA depending on the hospital protocols and policies; however, there is still controversy over the best choice. As the results of the retrieved articles indicated, propofol is the most common medication used for PSA in EDs due to the shorter time of induction, rapid recovery of consciousness, and fewer side effects. Etomidate and ketamine were also identified as other common sedatives applied for PSA.