Background: Opioids are commonly prescribed in the emergency department (ED) for the treatment of acute pain. Analgesic alternatives are being explored in response to an epidemic of opioid misuse. Low-dose ketamine (LDK) is one opioid alternative for the treatment of acute pain in the ED. Objectives: This systematic review and meta-analysis sought to quantify whether LDK is an effective and safe opioid alternative for acute pain reduction in adults in the ED setting. (PROSPERO Registration Number CRD42017065303). Methods: This was a systematic review of randomized controlled trials comparing intravenous opioids to LDK for relief of acute pain in the ED. Studies where the control group initially received opioids prior to ketamine were excluded. A research librarian designed the electronic search strategy. Changes in visual analog scale or numeric rating scale pain scales were analyzed to determine the relative effects of LDK and opioids in the treatment of acute pain. Results: Three studies met the criteria for inclusion in this meta-analysis. Compared to pain scale reduction with morphine, ketamine was not inferior (relative reduction = 0.42, 95% confidence interval = –0.70 to 1.54). No severe adverse events were reported in any study, but higher rates of nonsevere adverse events were observed with ketamine. Conclusions: Ketamine is noninferior to morphine for the control of acute pain, indicating that ketamine can be considered as an alternative to opioids for ED short-term pain control.