Background. Diarrhea is the leading cause of mortality among infants and children younger than 5 years of age in both underdeveloped and developing countries. Factors determining the occurrence of diarrhea in children are complex, and the relative contribution of each factor varies as a function of interaction between socioeconomic, environmental, and behavioral variables. Objectives. To assess diarrhea prevention practice and associated factors of diarrheal disease among caregivers who have under-five children in Enemay district, Ethiopia, 2018. Methods. Community-based cross-sectional study was done from June 1–30, 2018, among 398 caregivers who have under-five children, in the Enemay district that were selected by using the simple random sampling technique. A structured and pretested data collection tool was used to collect the data. Data were entered using EPI DATA version 4.2, and analysis was done using SPSS version 20 statistical package to be cleaned and analyzed. Descriptive analysis was done to describe study participants, and logistic regression (bivariable and multivariable) analysis was done to identify factors that have association with the dependent variable. The P value was less than 0.05. Results. A total of 398 with a response rate of 97% under-five caregivers were participated in this study. Nearly, half (48.7%) of the participants were in the age group 25–34. The study revealed that good practice of diarrhea prevention was 52.8%. This study was also identified that occupation (AOR: 3.922, 95% CI: 1.593, 9.657), family size (AOR: 0.088, 95% CI: 0.009, 0.916), and understanding on diarrhea (AOR: 0.237, 95% CI: 0.091, 0.613) were associated factors of diarrhea prevention practice of under-five children caregivers. Conclusion. This finding showed that diarrhea prevention practice among under-five children caregivers was low and prevention practice was significantly associated with caregivers’ awareness on frequency of diarrhea in a day, occupation, and family size in a house.