Background Colostrum avoidance is failure to feed first breast milk to a newborn baby for the first 2 to 3 days after delivery. The problem of avoiding colostrum is prevalent in Ethiopia. But it is not adequately addressed yet. Therefore, the purpose of this study was to assess prevalence of colostrum avoidance practices and associated factors among mothers of infants aged less than six months; and to explore barriers for colostrum feeding in ChenchaZuria District. Methods A community-based cross-sectional study supplemented with a qualitative study was conducted in August 2020. The quantitative data were collected from 674 mothers selected by systematic sampling using a structured questionnaire. Both bi-variable and multi-variable binary logistic regression analysis was used to identify factors associated with the colostrum avoidance practices. The statistical significance was declared at a p-value < 0.05. The qualitative data were collected using in-depth interviews from breastfeeding mothers and thematic analysis was done manually. Result The prevalence of the colostrum avoidance practice was 15.3% (95% CI: 11.4%- 18.2%). Late initiation of breastfeeding (AOR 4.15 95% CI 2.51–6.84), giving pre-lacteal feeding (AOR 3.16 95% CI 1.93–5.15), not using of postnatal care (PNC) service (AOR 1.79 95% CI 1.05–3.04), and having poor maternal knowledge regarding colostrum. (AOR 1.88 95% CI 1.14–3.08) were factors significantly associated with the colostrum avoidance practices. And in the qualitative part, cultural beliefs and misconceptions, community influence, and complementary feeding practices were found to be facilitators for the colostrum avoidance. Conclusion About one in seven mothers practiced colostrum avoidance. Factors that contributed to the colostrum avoidance practices were breastfeeding initiation, pre-lacteal feeding, PNC utilization, and maternal knowledge regarding colostrum. Thus, efforts to prevent colostrum avoidance practices should focus on strengthening and promoting PNC services utilization, timely initiation of breastfeeding, and improving awareness creation activities on the importance of colostrum feeding and risks of pre-lacteal feeding.