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Introduction: Ketamine can be particularly helpful in situations where the clinician is not able to administer opioids and require an alternate analgesic, such as for patients who are already on high-dose opioids, have a history of addiction, or for opioid-naïve children and adults. In this review, our goal was to obtain a comprehensive estimate of the efficacy and safety of low-dose ketamine (dose less than 0.5 milligrams per kilogram or equivalent) compared to opiates for the control of acute pain in the emergency setting. Methods: We conducted systematic searches in PubMed Central, EMBASE, MEDLINE, the Cochrane Library, ScienceDirect, and Google Scholar from inception until November 2021. We used the Cochrane risk-of-bias tool to assess the quality of included studies. Results: We carried out a meta-analysis with a random-effects model and reported pooled standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals depending on the type of the outcome. We analyzed a total of 15 studies with 1,613 participants. Half of them had high risk of bias and were conducted in the United States of America. The pooled SMD for pain score was −0.12 (95% CI −0.50–0.25; I2=68.8%) within 15 minutes, −0.45 (95% CI −0.84–−0.07; I2=83.3%) within 30 minutes, −0.05 (95% CI −0.41–0.31; I2=86.9%) within 45 minutes, −0.07 (95% CI −0.41–0.26; I2=82%) within 60 minutes, and after 60 minutes the pooled SMD was 0.17 (95% CI −0.07–0.42; I2=64.8%). The pooled RR for need of rescue analgesics was 1.35 (95% CI 0.73–2.50; I2=82.2%). The pooled RRs were as follows: 1.18 (95% CI 0.76–1.84; I2=28.3%) for gastrointestinal side effects; 1.41 (95% CI 0.96–2.06; I2=29.7%) for neurological side effects; 2.83 (95% CI 0.98–8.18; I2=47%) for psychological side effects; and 0.58 (95% CI 0.23–1.48; I2=36.1%) for cardiopulmonary side effects. Conclusion: Low-dose ketamine might have higher or equivalent efficacy and safety when compared to opioids for managing acute pain among patients presenting to the emergency setting. However, further studies are required to establish conclusive evidence, owing to the heterogeneity and poor quality of existing studies.