Due to overcrowding, personnel shortages, or problematic intravenous (IV) cannulation, acute pain management is often sub-optimal in emergency departments (EDs). The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of intranasal (IN) ketamine for adult acute pain in the emergency setting. We searched and identified studies up to 21 May 2021 via PubMed, Scopus, Web of Science, Cochrane Database, and Google Scholar. The random-effects model with 95% confidence intervals (CIs) was used to estimate mean differences (MDs) and odds ratios (ORs). The I² statistic and Cochran’s Q test were used to determine heterogeneity. The protocol was registered in PROSPERO (CRD42020213391). Seven randomised controlled trials were included with a total of 1760 patients. There was no significant difference in pain scores comparing IN ketamine with IV analgesics or placebo at 5 (MD 0.94, p = 0.26), 15 (MD 0.15, p = 0.74), 25 (MD 0.24, p = 0.62), 30 (MD −0.05, p = 0.87), and 60 (MD −0.42, p = 0.53) minutes. There was also no significant difference in the need for rescue analgesics between IN ketamine and IV analgesics (OR 1.66, 95% CI: 0.57−4.86, p = 0.35, I² = 70%). Only mild adverse effects were observed in patients who received IN ketamine. Our results suggest that IN ketamine is non-inferior to IV analgesics and may have a role in acute pain management among adults in the ED.