Background: Optimal breastfeeding is one of the best and cost-effective strategic interventions to prevent and reduce child death. Globally, it prevents 13% of childhood death, yearly. Few previous studies addressed the levels of domains of optimal breastfeeding practice separately, more emphasized the practice of urban-dwellers and employee mothers’ infants and focused on the practice of infants aged 6-24 months. This study assessed optimal breastfeeding practice and associated factors among infants aged 0-6 months in Boke district in rural eastern Ethiopia. Method: Community-based cross-sectional study was conducted among 390 randomly selected mother-infant pairs from February 01-30, 2018. Pretested-structured questionnaire was used to collect data from mother-infant pairs. Data were entered using EpiData version 3.1 and analyzed by SPSS version 24. Multivariable logistic regression analysis was used to identify factors associated with optimal breastfeeding practice. P-value<0.05 and AOR (95% CI) were used to report significance and association, respectively. Results: Optimal breastfeeding practice among infants aged 0-6 months was 55.9% (95%CI: 50.7%, 60.8%). Mothers’ age of 15-24 years (AOR=3.58, 95%CI: 1.06, 11.95) and 25-34 years (AOR=3.49, 95%CI: 1.08, 11.28), having formal education (AOR=2.98, 95%CI: 1.92, 4.62), facility delivery (AOR=1.96, 95%CI: 1.24, 3.12) and good knowledge about breastfeeding (AOR=1.82, 95%CI: 1.16, 2.86) significantly associated with optimal breastfeeding practice. Conclusions: Prevalence of optimal breastfeeding practice among infants of 0-6 months was low. Youth maternal age, institutional delivery and knowledge on breastfeeding were significant predictors of optimal breastfeeding practice. Promoting institutional delivery and enhancing maternal awareness about breastfeeding practice through existing healthcare services, formal education and Media-outlets would be essential to improve to prevent and reduce the burden of suboptimal breastfeeding practice in the communities.