Aim: This study was conducted to assess level of knowledge and practice of caregivers regarding prevention of early childhood caries in preschool children. Methods: A cross-sectional study was conducted among caregivers of preschool children. A consecutive sampling technique was used to recruit 399 caregivers based on sample size calculation. Data was collected based on clinical examination and previously validated questionnaires. Dental caries experiences were calculated by dmft index using WHO criteria for dental caries diagnosis. Statistical analysis: Data was statistically analyzed using the Statistical Package of Social Science Software program, version 23. Data presented using frequency and percentage for qualitative variables. Comparison between groups had been performed using Chi-square or Fisher's exact test for qualitative variables. P-Values less than 0.05 were considered statistically significant. Results: This study highlights that caregivers who have good knowledge about oral health are mothers, high level of education, high family income, caregivers of child with dmft < 7. Additionally, family with high income, caregivers of children aged < 4 years and caregivers of the children with dmft < 7 and caregivers with sufficient knowledge each has higher practice regarding children oral health Conclusion: the majority of caregivers (64.4 %.) had sufficient knowledge related to prevention of ECC. In spite of that most of them (63.2%) were having low skills to prevent ECC. So, oral health education programs should be targeted to caregivers especially the lower socioeconomic groups to motivate them to take care of their child oral health and improve their practice..