Hypoxic ischemic encephalopathy (HIE) is a serious condition that results from reduced oxygen supply and blood flow to the brain, leading to brain injury and potential long-term neurodevelopmental impairments. This study aimed to identify the maternal and neonatal factors that are associated with HIE among newborns in Ethiopia. An unmatched-control study was conducted in fifteen public hospitals in Southern Nation Nationalities and the Peoples Regional State of Ethiopia. Data were collected from 515 newborns with their index mothers (175 cases and 340 controls) using a structured questionnaire and clinical records which were created and managed by Kobo software for mobile-assisted data collection. Clinical biomarkers were used to diagnose Hypoxic ischemic encephalopathy. Logistic regression analysis was performed to identify the factors associated with Hypoxic ischemic encephalopathy. Maternal education, ultrasound checkup status, gestational age at delivery, mode of delivery, and labor duration were significantly associated with Hypoxic ischemic encephalopathy. Newborns born to illiterate mothers (AOR= 1.913, 95%CI: 1.177, 3.109), those whose mothers did not have an ultrasound checkup during pregnancy (AOR= 1.859, 95%CI: 1.073, 3.221), those who were born preterm (AOR= 4.467, 95%CI: 1.993, 10.012) or post-term (AOR= 2.903, 95%CI: 1.325, 2.903), those who were delivered by cesarean section (AOR= 7.569, 95%CI: 4.169, 13.741), and those who were delivered after prolonged labor (AOR= 3.591, 95%CI: 2.067, 6.238) had higher odds of developing Hypoxic ischemic encephalopathy than their counterparts. This study provides valuable insights into the risk factors for Hypoxic ischemic encephalopathy among newborns in Southern Ethiopia. Improving maternal education and health care services during pregnancy and delivery may help reduce the incidence and severity of Hypoxic ischemic encephalopathy. Future research should use laboratory or imaging investigations, including private health institutions, and explore the mechanisms and outcomes of Hypoxic ischemic encephalopathy.