BackgroundEven though child mortality decreased greatly (44%, since 1990), children in developing countries are eight times more likely to die before they attain their five years birthday. When comparing under-five mortality around the world, the African including Ethiopia and Southeast Asian regions showed an uneven child death rate. Therefore, this study was aimed to identify the potential determinant factors of under-five mortality in the Amhara regional state of Ethiopia.MethodsStatistics from a national representative cross-sectional survey of the Ethiopian Demographic and Health Survey (EDHS) of the year 2016 were used. Data was collected from the population of all under-five children in randomly selected enumeration areas of the Amhara region of Ethiopia. To investigate the relationship between the dependent variable (under-five mortality) and various independent factors, inferential statistics such as binary logistic regression and multiple logistic regressions were used. In multivariable analysis, statistically significant variables in binary logistic regression analysis, i.e. (p-value 0.250), were entered, and P-value 0.050 was considered significant at 95% CI.ResultsThe survey was included 977 children under the age of five and more than half of children in the family (68%) were ≤ 4. The findings showed that children whose mothers had no formal education were 2.59 times more likely to die than children whose mothers had formal education [AOR: 2.59(1.12–5.99)]. Similarly, children who did not receive breastfeeding from their mothers were 3.61 times more likely to die than children who received breastfeeding from their mothers [AOR: 3.61(1.83–6.19)].Conclusion and RecommendationThe number of children in the family, as well as the mother’s educational status and current breastfeeding status, were all found to be important factors in under-five mortality in the study area. As a result, the potential determinants of under-five mortality should be addressed as part of a program targeted at lowering childhood mortality.