ABSTRACT Background: Although lacks an exact definition, neonatal sepsis can be defined as systemic inflammatory response syndrome in the presence of an infectious process occurring within 28 days of life. Every year an estimated 2.9 million deaths worldwide were due to sepsis (44% of them in children under 5 years of age) and one-quarter of these are due to neonatal sepsis. It is a global problem, particularly in resource-limited countries like Ethiopia resulting in significant neonatal morbidity and mortality. This study showed continued high burden of neonatal sepsis and its significant contributors are not consistently the same requiring continuous research to be done in different places. Objectives: The objective of this study is to assess neonatal sepsis and associated factors of neonates admitted to the neonatal ward at Tibebe Ghion specialized hospital in BahirDar city, Northwest Ethiopia from February 1, 2022, to May 30, 2022. Methods: Institution-based cross-sectional study was conducted among 357 neonates from February 1 to May 30, 2022. The Participants were selected using a systematic random sampling technique. The interviewer-administered structured questionnaire and checklist were used to collect the data. The collected data was entered into EPI data version 4.6 and exported to SPSS version 25 for analysis. Descriptive and binary regression analysis was done. A binary logistic regression model was used to recruit regression analysis. On the multivariable analysis, variables with a p-value <0.05 were considered statistically significant. Results: The proportion of neonatal sepsis was 35.6%, 95%CI (30.7-40.5). Being male, [AOR = 1.9; 95% CI (1.1, 3.30)], primi parity (AOR=2.8; 95%CI(1.2-6.5)), duration of labor (13-24 hours) [AOR=1.9; 95% CI[( 1.1-9.3))]], Birth weight [(<1500g (AOR=3.2 95%CI (2.7-27 )) , (1500 and 2500 g [AOR = 1.5; 95% CI[((1.1-8.6)))] were positively associated with neonatal sepsis. Whereas being delivered at health center [AOR=0.45; 95% CI ((0.24-0.82)) p=0.012] was negatively associated with neonatal sepsis. Conclusion and Recommendation: This study revealed that the burden of neonatal sepsis is still high. Being male sex, duration of labor between 13-24 hours, low birth weight, and place of delivery (health center) were identified risk factors significantly associated with neonatal sepsis. Therefore, follow-up of mothers during delivery with intent to shorten duration of labor, provision of health care services including measurement of maternal body mass index (BMI), assessing maternal comorbid conditions, and advice on maternal prenatal nutrition is paramount.