Introduction: Generic drugs have the same chemical formula as brand product and they are bioequivalent to the originator product. Insufficient knowledge of healthcare professionals about generics causes’ reduced utilization of these drugs. Therefore, this study narrows the knowledge gap and the findings assist policy makers regarding generic prescribing in the future. Aim: To assess knowledge, Attitude and practiceof pharmacy professionals toward generic products. Method: The study was conducted in all medicine retail outlets in Mekelle city, from April 10, 2016-May 12, 2016. Facility based cross -sectional study was used and the data collection tool were self-administered questionnaire. Statistical test binary logistic regression has been done to determine predictors of knowledge and attitude toward generic medicines. Results: From the current study more than half of the respondents 52.9% (agree=32.2%, 20.7% strongly agree) claimed that they have had knowledge on the concept of generic medicine. Pharmacy professionals with experience of from 2 to 5 years (AOR=25.620 [1.954-335.896) and those with more than 5 years (AOR=106.543 [2.375-4779.542) were more likely to have positive attitude toward generic medicines compared to those with work experience of up to 2 years. Conclusion: More than half of the study participants have had knowledge on the concept of generic medicine and their right to perform generic substitution. The professionals with more experience in the sector could have better view on generic product.