Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department. This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded. Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15 min of PSA in the group PF was significantly higher than the group PK. It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments.