Objective(s): Quantify antimicrobial therapy (AMT) use in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia (HIE/TH). Study design: Newborns with HIE/TH were identified from the Children’s Hospital Neonatal Database (CHND). Early infection (onset ≤7 days of life) was defined as “confirmed” (culture proven) or “suspected infection” (culture negative but treated) and compared with a “no infection” group. Results: 1501/1534 (97.8%) neonates received AMT. 36 (2.3%) had confirmed, 255 (16.6%) suspected, and 1243 (81.0%) had no infection. The median (IQR) AMT duration was 13 (8–21), 8 (7–10), and 3 (3–7) days for the three groups, respectively (p < 0.001). AMT duration of use varied significantly across centers, adjusted for covariates (OR 1.88, 95% CI: 1.43–2.46). Conclusion(s): Incidence of early confirmed infection in neonates with HIE/TH (23/1000) is significantly higher than reported rates of early onset sepsis in term and near term infants (0.5–1.0/1000 live births). Antimicrobial-stewardship opportunities exist in infants with negative cultures.