Background <p>Epidural anesthesia stands out as the most commonly employed approach for labor analgesia, frequently complemented by various local anesthetics, and the analgesic effectiveness and safety profiles of distinct local anesthetic regimens are different. To compare the efficacy and adverse reactions of different local anesthetic regimens in relieving labor pain by performing a network meta-analysis.</p> Methods <p>We systematically searched four electronic databases (PubMed, EMBASE, Web of Science, and Cochrane Library) for randomized controlled trials from the inception of the databases up to March 3, 2025. Included in the study were patients aged 18 to 35 years who underwent painless delivery under epidural anesthesia.</p> Results <p>The meta-analysis included a total of 59 studies involving 6972 patients. The combination of Ropivacaine_Dexmedetomidine_Sufentanil (Rop_Dex_Suf) was the most effective and fast in reducing Visual Analog Scale (VAS) scores at 30&#xa0;min after block, compared to most other anesthesia schemes. Labor pain lasted for the longest time with Ropivacaine_Dexmedetomidine(Rop_Dex). Meanwhile, Bupivacaine_Pethidine(Bpv_Pet), Bupivacaine_Dexmedetomidine(Bpv_Dex), Fentanyl(Fen), and Bupivacaine_Diamorphine(Bpv_DiaMor) had the lowest incidence of nausea, vomiting, hypotension, and pruritus. Besides, Bupivacaine_Dexmedetomidine(Bpv_Dex), Ropivacaine_Dexmedetomidine(Rop_Dex), and Ropivacaine_Dexmedetomidine_Sufentanil (Rop_Dex_Suf) have demonstrated outstanding analgesic efficacy and safety.</p> Conclusions <p>Our study demonstrates that the combination of ropivacaine, dexmedetomidine, and sufentanil is the most effective regimen for alleviating labor pain. Nonetheless, given the limited number of studies on certain protocols, additional high-quality, large-scale randomized controlled trials (RCTs) are anticipated to substantiate our conclusion in the future.</p> PROSPERO registration number <p>CRD42023459538.</p> Clinical trial number <p>Not applicable.</p>