Background: Exclusive breastfeeding is an important strategy for improving child health. However, the practice of exclusive breastfeeding among employers is very low in developing countries including Ethiopia and its level is unknown in study district. Understanding level of Knowledge and Practice of employed mothers towards exclusive breastfeeding /EBF/ in the study area was needed to develop effective interventions to improve the rates of EBF and thus reduce infant mortality. Objective: The objective of this study was to assess the level of knowledge and practice among employed mothers towards exclusive breastfeeding and its associated factors in Mecha district, Amhara Region, North West Ethiopia 2018. Methods: Cross-sectional study design was conducted on 449 randomly selected employed mothers in Mecha district from April to June 2018. Stratified random sampling technique was used as sampling technique considering employment status as strata. Data were analyzed using software program of a statistical package for social sciences (SPSS) version 23. Information about the scores in a sample was presented in frequency tables. Multivariable logistic regression was used to determine predictors of Knowledge and practice. Result: A total of 449 mothers who had children of age 6-23 months in Mecha district were enrolled with a respond rate of 95.54 %.The study revealed 92.1% (95% CI: (89.5-94.6)) of participants had good knowledge. However, only 38.5 %( 95% CI: (33.8- 42.9)) employed mothers were breastfeed their babies exclusively. Certain factors statistically associated with exclusive breast feeding Among these maternity leave taken(AOR=0.31, 95% CI:(0.10-0.91), p-value =0.03)),mothers‟ level of education(AOR=2.97, 95% CI: (1.66-5.34), p-value<0.01)), support from husbands(AOR=0.26, 95% CI ( 0.14-0.47), p-value <0.00)), actual time come back to their work(AOR=0.21; 95% CI: (0.08-0.51), p-value <0.01)) , the knowledge of employed were statistically significant for Practice towards the exclusive breast feeding. Conclusions and recommendations: The Knowledge and practice of employed mothers towards exclusive breast feeding had affected by the number of predictors. Exclusive breastfeeding practice among employed mothers was low. Orientation about use and advantage of exclusive breast feeding should be given for employed mothers. It is advisable to give some flexible working hours for breast feeding mothers.