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Background/importance Local anesthetic (LA) mixtures are used in peripheral nerve blocks (PNB) to improve onset, though study results remain conflicting.Objective This systematic review and meta-analysis compared the efficacy outcomes of long-acting LA to their mixture with shorter-acting LA in ultrasound-guided PNB. The primary outcome was sensory block onset.Evidence review We searched WoS, Scopus, MEDLINE, EMBASE, BVS/LILACS, and Cochrane databases from 1998 to 2024 for randomized controlled trials (RCTs). We conducted a random-effects meta-analysis, evaluated the risk of bias (RoB) with RoB 2.0, performed sensitivity analyses, assessed non-reporting bias with DOI plots and Luis Furuya-Kanamori index, and evaluated strength of evidence with Grading of Recommendations Assessment, Development and Evaluations.Findings We included 10 RCTs (516 participants). Mixture of LA may have no effect on sensory block onset (mean difference (MD) −1.62 min, 95% CI: −4.04 to 0.81; I 2=81.50%, 95% CI: 62.82% to 90.80%; prediction interval (PI)=−7.78 to 4.55; very low certainty) and motor block onset (MD −5.60 min; 95% CI: −14.54 to 3.33, I2=98.89%, 95% CI: 98.50% to 99.18%; PI=−31.90 to 20.69; very low certainty), while it may reduce the duration of sensory block (MD −2.16 hours, 95% CI: −4.16 to −0.17; I2=90.77%, 95% CI: 84.22% to 94.60%; PI=−7.24 to 2.92; very low certainty).Conclusions LA mixtures may not affect sensory and motor block onset in ultrasound-guided PNB but could shorten the duration of sensory blockade.