ObjectiveThis study was conducted with the aim of assessing mothers' level of knowledge of neonatal danger signs and its associated factors in Mekedella woreda, Northeast Ethiopia. Study designThis is a community-based cross-sectional study. MethodsThe study was conducted among 757 mothers who were selected by stratified simple random sampling between November 1, 2017, and December 30, 2017. A structured interviewer-administered pretested questionnaire was used to collect the data. Data were entered into EpiData, version 3.1, and then exported into SPSS (statistical package for social science), version 20, for analysis. Independent predictors of women's level of knowledge were identified by multivariable logistic regression analysis. ResultsIn total, only 28.2% of mothers were knowledgeable about neonatal danger signs. Significant predictors of a good level of knowledge on newborn danger signs included those who attended secondary education, were urban residents, attended 2–3 antenatal care visits, had an institutional delivery, attended postnatal care visit(s), had a higher decision-making ability to seek neonatal health care, completed up-to-date immunisation of the infant, had heard about neonatal danger signs from health workers and had a history of neonatal death. ConclusionsEducating women, increasing mothers' health service use and providing health education for mothers who attend pregnancy-related services showed a positive impact on their knowledge of neonatal danger signs and should therefore be promoted.