Objective: This systematic review and network meta-analysis aimed to compare and evaluate the efficacy and safety of five medications, Dupilumab, Tralokinumab, Upadacitinib, Baricitinib, and Abrocitinib, for the treatment of adolescent atopic dermatitis, in order to provide decision support to support clinical decision-making by developing more scientifically-grounded and effective treatment strategies. Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science (WoS), and the Cochrane database to collect randomized controlled trials (RCTs) and Phase 3 clinical trials up to April 13, 2024. Supplementary data were retrieved from trial registries, and researchers contacted study authors and pharmaceutical companies when necessary to obtain complete data. Inclusion criteria comprised treatment studies for moderate to severe atopic dermatitis in adolescents aged 12 and above, with outcome measures including efficacy and safety assessments. Data extraction and risk bias assessment were independently performed by two researchers, using Excel for data extraction and the netmeta package in R software for network meta-analysis. Sensitivity analysis and bias risk assessment were conducted to validate the robustness and credibility of the results. Our research protocol was registered in PROSPERO (CRD42023480597) and did not require approval from an institutional review board or written informed consent. Results: In the primary efficacy outcome measures, Upadacitinib 30mg/d, Upadacitinib 15mg/d, and Dupilumab 300mg/2w demonstrated excellent efficacy in EASI75 compared to placebo, significantly outperforming other medications and placebo. Dupilumab 300 mg/2w, Upadacitinib 30 mg/d, and Upadacitinib 15mg/d showed excellent treatment effects in IGA0/1. Among the outcome measures for improvement in itch severity rating PP-NRS4, Dupilumab 300mg/2w and Tralokinumab 300mg/2w showed the highest efficacy values. Compared to these medications, Baricitinib 1mg/d exhibited weaker performance across all three indicators, particularly in EASI75 and IGA0/1, with effects approaching no significant difference. Due to limited sample sizes, estimates for treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and drug-induced adverse events (DIAEs) safety indicators were unstable, preventing strong conclusions on safety outcomes. Further studies with long-term follow-up and larger sample sizes are required to explore the safety of these five medications in the adolescent population. Conclusion: Upadacitinib and Dupilumab demonstrate strong efficacy and symptom improvement in the treatment of moderate to severe atopic dermatitis in adolescents, particularly in reducing the severity of skin lesions and itchiness. Therefore, these medications should be considered as primary treatment options for adolescents with atopic dermatitis.