Background: Despite a global decline in under- five deaths, the rate remains slow in developing countries, around 4–9 million newborns develop birth asphyxia, the third cause of under-five deaths, causing irreversible neurological damage (25%). Globally, neonates account for 45% of under-five deaths, low-countries account for 23%, Ethiopia accounts for 34%, and birth asphyxia causes about 23-40% of neonatal death. Despite this evidence that birth asphyxia was a leading and preventable cause of neonatal morbidity and mortality in developing countries, birth asphyxia determinants were not systematically investigated and limited data in Ethiopia, particularly in the study area, and early identification and management of its main factors would reduce the problem. Thus, this study aimed to identify the determinants of birth asphyxia among newborns at Debre Markos referral hospital, Northwest Ethiopia. Methods: This research followed a hospital-based an unmatched case-control study design at Debre Markos referral hospital, Northwest Ethiopia, among 372 newborns (124 asphyxia cases and 248 nonasphyxia controls) from August 1/2019 to October 30/ 2019. Ethical approval was received from the Debre Markos University Board of Institutional Review. A pretested structured questionnaire was used to collect data. Data were entered in Epi-data version 3.1 and transferred to STATA version 14.0 for analysis and logistic regression was used to determine possible factors of candidate variables with p-value <0.2 for the final model. Birth asphyxia determinants were considered using an adjusted odds ratio of 95% CI and p-value <0.05. Results: Prolonged labour (>12 hours) [OR=3.10], meconium stained amniotic fluid [OR=6.80], assisted vaginal delivery (vacuum or forceps) and C/S delivery [OR= 3.42], gestational age < 37 weeks [OR= 3.72], non-cephalic presentation (OR: 2.43), cord prolapse [OR=2.95], premature rupture of membrane [OR=12.27] were predictors variables. Conclusion: In this study, prolonged labor (>12 hours), meconium-stained amniotic fluid, assisted vaginal delivery, gestational age < 37 weeks, non-cephalic presentation, cord prolapse and premature rupture of membrane were determinants of birth asphyxia. Therefore, to reduce neonatal mortality associated with birth asphyxia, attention should be given to holistic pregnancy, labor and delivery care, and post-natal care. Furthermore, intervention strategies aimed at reducing birth asphyxia should target the identified factors.