Musculoskeletal (MSK) injuries are one of the most frequent reason for pain-related evaluation in the emergency department (ED) in children. There is still no consensus as to what constitutes the best analgesic for MSK pain in children. However, ibuprofen is reported to be the most commonly prescribed analgesic and is considered the standard first-line treatment for MSK injury pain in children, even if it is argued that it provides inadequate relief for many patients. The purpose of this study was to review the most recent literature to assess the efficacy of ibuprofen for pain relief in MSK injuries in children evaluated in the ED. We performed a systematic review of randomized controlled trials on pharmacological interventions in children and adolescents under 19 years of age with MSK injuries according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome was the risk ratio for successful reduction in pain scores. Six studies met the inclusion criteria and provided data on 1028 children. A meta-analysis was not performed since studies were not comparable due to the different analgesic treatment used. No significant difference in term of main pain score reduction between all the analgesics used in the included studies was noted. Patients who received oral opioids had side effects more frequently when compared to children who received ibuprofen. The combination of effect on pain relief and tolerability would suggest ibuprofen as the initial drug of choice in providing relief from mild-to-moderate MSK pain in children in the ED. The results obtained in this review and current research suggest that there's no straightforward statistically significant evidence of the optimal analgesic agent to be used. However, ibuprofen may be preferable as the initial drug of choice in providing relief from MSK pain due to the favorable combination of effectiveness and safety profile. In fact, despite the non-significant pain reduction as compared to children who received opioids, there are less side effect associated to ibuprofen within studies. The wide range of primary outcomes measured in respect of pain scores and timing of recorded measures warrants a future standardization of study designs.