Background: Prelacteal feeding is one of the major harmful newborn feeding practices and is top on the list of global public health concerns. The practice deprives newborns of valuable nutrients and protection of colostrum and exposes them to preventable morbidity and mortality. Studying the prevalence and factors influencing the prelacteal feeding practice of mothers will help program managers and implementers to properly address broad major public health problems. Therefore, this study aims to investigate the prevalence of prelacteal feeding practices and its associated factors among mother-infant dyads in the Debre Berhan district of North Shoa administrative zone, central Ethiopia. Methods: A community-based cross-sectional study design was conducted from January through to April 2014 among 634 mother-infant dyads. The data were entered into EPI Info version 3.5.1. (CDC, Atlanta, Georgia). All statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) research IBM version 20.0. The prevalence of prelacteal feeding was determined using the 'recall since birth' method. Multi-variable logistic regression analysis was employed to control confounders in determining the association between prelacteal feeding practices and selected independent variables. Adjusted Odds Ratio (AOR), with 95% Confidence Interval (CI) and P < 0.05 was used to claim statistical significance. Results: The prevalence of prelacteal feeding practice was 14.2% (95% CI: 11.00-17.00%). Slightly greater than half, 48 (53.3%) of prelacteal fed newborns were given butter. Home delivery was a major risk factor for practicing prelacteal feeding. Mothers who delivered their indexed infant at home practiced prelacteal feeding over four folds more than mothers who delivered in a health institution (Adjusted Odds Ratio (AOR) 4.70; 95% CI: 2.56-8.60, pvalue = 0.001). Mothers who did not initiate breastfeeding within an hour were six times more likely to practice prelacteal feeding (AOR 5.58; 3.21-9.46, p-value = 0.001). Similarly, with regards to the occupation of mothers, farmers practiced prelacteal feedings (AOR 4.33; 95% CI: 1.73-10.81, p-value = 0.002) up to four folds more than their counterpart housewives. Mothers who can read and write are 54% less likely to practice prelacteal feeding than their counterpart, illiterate mothers, with (AOR 0.46; 95% CI: 0.22-0.98, p-value = 0.044).