Background Generic medicines are similar to innovator medicine in terms of safety, quality, efficacy, dosage form, strength, and route of administration. They have the same therapeutic use to innovator medicines and available at a far lower price. However, health professionals' poor knowledge and attitude may limit its utilization. The present study aimed at assessing the knowledge, attitude, and practice of pharmacy professionals towards generic medicines in Harar city, Eastern Ethiopia. Methods A cross-sectional survey was conducted among community pharmacists in Harar city. A self-administered thirty-three item questionnaire on Knowledge, attitude, and practice of community pharmacists was utilized. Logistic regression analysis was performed to predict the determinants of knowledge and attitude of pharmacists. An odds ratio at 95% confidence interval along with a p-value < 0.05 was considered significant. Results Among 80 community pharmacists’ approached, 74 completed the survey, providing a response rate of 92.5%. Sixty-seven percent of the respondents knew that generic drugs are bioequivalent to brand drugs and claimed generic medicines are cheaper (86.5%). Nearly half (48.6%) of participants believe that generic medicines are less effective and slower in the onset of action (58.1%). More than half (54.1%) of study participants revealed their lack of belief in generic medicine as a factor hindering the selection and dispensing of generic medicines. In multivariate logistic regression, experience in community pharmacy practice (Adjusted odds ratio (AOR = 2.18, 95%CI: 1.21–63.1) and Sex (AOR = 3.88, 95%CI: 2.12–39.62) were significantly associated with knowledge and attitude toward generic medicines, respectively. Conclusion The current study revealed that there is a gap in the knowledge and attitude of community pharmacists towards generic and brand drugs. More than averages of the respondents have known the concept of generic medicine including their right to perform generic substitution and had a positive attitude toward generics. Female pharmacists were more likely to have a positive attitude and the overall knowledge was higher in those who have more than 5 years of work experience.