Procedural sedation is routinely performed for procedures in the emergency department (ED). Propofol is a commonly used sedative, frequently combined with an opioid or low-dose ketamine as an analgesic. However, there is still controversy on the optimal combination of agents in current guidelines. The objective of this systematic review is to identify and present studies comparing low-dose ketamine to opioids when combined with propofol for procedural sedation in the ED and to describe the dosing regimen, observed efficacy, and side effects. For this systematic review, following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, EMBASE and PubMed databases were searched. Studies comparing propofol with opioids versus propofol with low-dose (es)ketamine in patients undergoing procedural sedation for procedures in the ED were included. Analyses were descriptive because of the high heterogeneity among included studies. The outcomes were dosing regimen, efficacy of analgesia, efficacy of sedation depth, efficacy of recovery and (adverse) events. We included four out of 2309 studies found in the literature search. Overall, the studies had a low risk of bias, but the Grading of Recommendations Assessment, Development, and Evaluation evidence profile was downgraded due to the imprecision and inconsistency of the studies. All studies compared low-dose ketamine with fentanyl. Dosing ranged from 0.3 to 1.0 mg/kg (ketamine), 1.0-1.5 μg/kg (fentanyl) and 0.4-1.0 mg/kg (propofol). The efficacy of analgesia was measured by two studies, one favoring the fentanyl group, and one favoring the ketamine group. The efficacy of sedation depth was measured by one study, with the fentanyl group having a deeper sedation score. Two studies showed shorter recovery time with low-dose ketamine. One study showed a higher incidence of cardio-respiratory clinical events and interventions in the fentanyl group. Two studies showed significant differences of overall sedation events in the fentanyl group. One study did not find any significant differences of the incidence of sedation events. This systematic review did not provide sufficient evidence that the combination of low-dose ketamine and propofol is associated with a shorter recovery time and fewer sedation events compared to the combination of opioids and propofol.