Despite the high burden of neural tube defects (NTD) in eastern Ethiopia, there is no evidence that it is related to maternal dietary practice. The aim of the present study was to compare dietary practice between women who gave birth to newborns with and without NTDs. A comparative cross-sectional study was performed on a total of 276 (138 in each group) mothers who delivered neonates with or without NTD. Study participants were selected from three hospitals found in the eastern part of Ethiopia. The dietary practice was determined using the indicators including meal frequency, dietary diversity score (DDS), food variety score (FVS) and consumption of animal source food (ASF) generated from the dietary data collected using validated and pre-tested Food Frequency Questionnaire (FFQ). A multivariable logistic regression model was fitted to isolate independent predictors of dietary practices. The prevalence of good dietary practice was 29 % (95 % CI 23·6 %, 34·3 %). There was a significant difference in dietary practices (P = 0·034), in FVS (P = 0·01), in DDS (P = 0·045) between the two groups. In multivariable logistic regression, independent predictors of having good dietary practice were: not being the mother of a newborn with NTDs [adjusted odds ratio (AOR) 2·1, 95 % CI 1·07, 4·1], being from a rural residence area (AOR 0·29, 95 % CI 0·1, 0·7) and being illiterate (AOR 0·16, 95 % CI 0·03, 0·8). The present study found that dietary practice is associated with the development of NTDs. Nutrition education, food fortification and supplementation are needed to address this issue, and further research is needed to explore the mechanism.