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Objective To systematically evaluate the differential long-term outcomes—including mortality, severe disability, and specific neurodevelopmental domains (language, learning, memory)—associated with various therapeutic hypothermia strategies for moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) through a comprehensive review and meta-analysis. Methods A systematic search was conducted across PubMed, Embase, and the Cochrane Library up to December 2023, supplemented by gray literature and reference tracking. Randomized controlled trials (RCTs) and prospective cohort studies involving neonates ≥36 weeks' gestation with moderate-to-severe HIE treated with therapeutic hypothermia were included. Data extraction covered study characteristics, outcome data, and risk of bias indicators. The subgroup analysis, sensitivity analysis, and assessment of publication bias were carried out. Results A total of 11 studies involving 1,466 neonates were included. The pooled composite endpoint rate (mortality + severe disability) after therapeutic hypothermia was 39.2% (95% CI: 32.7%–46.1%). Subgroup analysis revealed that whole-body cooling demonstrated superior efficacy compared to selective head cooling (RR = 0.71, P = 0.03), and lower target temperatures (≤34 °C) further improved outcomes ( P = 0.04). Limited domain-specific data showed receptive language delays (18%), expressive language delays (22%), and working memory impairments (15%) in survivors without severe disability. Studies with >18-month follow-up showed a non-significant trend toward higher disability detection. The overall quality of evidence was medium, with most studies having a moderate risk of bias and low applicability concerns. No significant publication bias was detected ( P = 0.08). Conclusion Therapeutic hypothermia reduces the combined risk of mortality and severe disability in moderate-to-severe neonatal HIE. Whole-body cooling and target temperatures of 33–34 °C may optimize outcomes, but extreme hypothermia (≤32 °C) is associated with increased mortality, necessitating careful monitoring of adverse events. Further research is needed to optimize protocols and characterize neurodevelopmental outcomes in specific domains (e.g., language, memory).