Background Opioids are often prescribed for acute pain to patients discharged from the emergency department (ED), but there is a paucity of data on their short‐term use. The purpose of this study was to synthesize the evidence regarding the efficacy of prescribed opioids compared to nonopioid analgesics for acute pain relief in ED‐discharged patients. Methods MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL, and gray literature databases were searched from inception to January 2023. Two independent reviewers selected randomized controlled trials investigating the efficacy of prescribed opioids for ED‐discharged patients, extracted data, and assessed risk of bias. Authors were contacted for missing data and to identify additional studies. The primary outcome was the difference in pain intensity scores or pain relief. All meta‐analyses used a random‐effect model and a sensitivity analysis compared patients treated with codeine versus those treated with other opioids. Results From 5419 initially screened citations, 46 full texts were evaluated and six studies enrolling 1161 patients were included. Risk of bias was low for five studies. There was no statistically significant difference in pain intensity scores or pain relief between opioids versus nonopioid analgesics (standardized mean difference SMD 0.12; 95% confidence interval CI −0.10 to 0.34). Contrary to children, adult patients treated with opioid had better pain relief (SMD 0.28, 95% CI 0.13–0.42) compared to nonopioids. In another sensitivity analysis excluding studies using codeine, opioids were more effective than nonopioids (SMD 0.30, 95% CI 0.15–0.45). However, there were more adverse events associated with opioids (odds ratio 2.64, 95% CI 2.04–3.42). Conclusions For ED‐discharged patients with acute musculoskeletal pain, opioids do not seem to be more effective than nonopioid analgesics. However, this absence of efficacy seems to be driven by codeine, as opioids other than codeine are more effective than nonopioids (mostly NSAIDs). Further prospective studies on the efficacy of short‐term opioid use after ED discharge (excluding codeine), measuring patient‐centered outcomes, adverse events, and potential misuse, are needed.