Background <p>Despite the improvements made to decrease neonatal mortality, neonatal mortality remained high in Ethiopia, contributing to approximately 70% of infant mortality. Data on the clinical profiles, outcomes, and predictors of mortality of mechanically ventilated neonates in our country are scarce. This research was performed to determine the outcomes and predictors of mechanically ventilated neonates.</p> Methods <p>This prospective observational study was conducted consecutively among all neonates who were mechanically ventilated in the neonatal intensive care unit of Ayder Hospital from October 2020 to July 2021. Neonates with birth weight &lt; 1000&#xa0;g or gestational age &lt; 28 weeks (labeled as abortion in our setup), and neonates with fatal congenital anomalies were excluded from the study. The data were entered, cleaned, and analyzed in SPSS version 23. Descriptive statistics were presented as frequencies and percentages. Correlations were measured by chi-square tests, and a p-value less than 0.05 was considered to indicate statistical significance.</p> Result <p>A total of 41 neonates were enrolled. Only 12.2% (5/41 patients) of the intubated and ventilated neonates survived, 26 (63.4%) neonates were male, with an M: F ratio of 1.7:1. The mean gestational age and birth weight of the neonates were 37.25 ± 3.95 weeks and 2700.85 ± 806.82&#xa0;g, respectively. The main clinical indication for intubation was apnea (65.85%), followed by low saturation on CPAP or head hood and gasping. The most common disease was sepsis (41.46%), followed by asphyxia and meconium aspiration syndrome. Tube block and hospital-acquired infection were the most common complications during ventilation. Tube block and high PIP were significantly associated with mortality (<i>P</i> &lt; 0.05).</p> Conclusions <p>The mortality rate of mechanically ventilated neonates was significantly high. Proper tube care and mechanical ventilation settings are important for improving survival.</p>