Background Respiratory distress contributes significantly to mortality and morbidity in infants. The incidence of noninvasive ventilation failure is remarkably high. There is limited data available regarding noninvasive ventilation failure in Ethiopia. Therefore, this study aimed to identify determinants of noninvasive ventilation failure among neonates with respiratory distress admitted to the intensive care unit in Addis Ababa, Ethiopia in 2022. This study was conducted from November 11, 2021, to January 30, 2022. A total of 237 charts (79 cases and 158 controls) were selected by a simple random sampling technique. Cases were defined as neonates who failed with noninvasive ventilation support while controls were successfully managed with noninvasive ventilation support. The data were abstracted from the facility-based data abstraction form. The data were cleaned, entered into Epidata version 4.4, and exported to SPSS version 25.0 software for analysis. Both binary and multiple logistic regression analyses were used to identify the determinants of noninvasive ventilation failure in neonates with respiratory distress with an adjusted odds ratio (AOR) with a 95% confidence level at P value < .05 used to declare determinants of a noninvasive ventilation failure. The mean birth weights of the neonates were 2.87 ± 0.85 SD kilograms and the mean gestational age was 35.02±2.66 SD. The current study determined that the incidence of noninvasive ventilation failure among neonates with respiratory distress was 20/100 per person-year in 2021. This study identified that determinants of noninvasive ventilation failure among neonates with respiratory distress were: very preterm neonates (AOR = 2.99 [95%CI: 1.11–8.12]); comorbid illness in mothers (AOR = 3.13 [95%CI: 1.55–6.33]), initiation of noninvasive ventilation at admission to the newborn intensive care unit (AOR = 2.63 [95%CI: 1.24–5.59]); oxygen saturation (SpO2) <85 and 85–93 SpO2 (AOR = 3.11 [95%CI: 1.32–7.32]) and (AOR = 2.75 [95%CI: 1.17–6.44]), Apgar score at 5 min <7(AOR = 3.19 [95%CI: 1.48–6.89]), and noninvasive ventilation through a home-made CPAP (AOR = 4.09 [95%CI: 1.82–9.20]), respectively. Conclusion and Recommendation The incidence rate of noninvasive ventilation failure among neonates is very high with identified determinants of noninvasive ventilation failures being comorbidity illness of the mother, Apgar score, Oxygen saturation at admission in %, ventilator modality of homemade CPAP, and initiation time of noninvasive ventilation. Therefore, policymakers and health planners would be better emphatically considering these identified determinants during neonatal training and guideline development for better neonatal noninvasive ventilation outcomes.