Background: Drugs have become one of an essential component of healthcare systems worldwide. However, there is a concern for their safety. Adverse drug reaction (ADR) is common during usual clinical practice and it is associated with increased morbidity, hospitalization and mortality. Objective: To assess knowledge, attitude, and practice of healthcare professionals (HCPs) towards ADRs reporting at inpatient wards of Tikur Anbessa Specialized Hospital (TASH), Ethiopia. Methods: Hospital based descriptive cross-sectional study was conducted among 280 HCPs at the inpatient wards of TASH. The data required for the present study was collected using self-administered structured questionnaire and samples were selected through both stratified and systematic random sampling methods, where the type of profession was used as a stratum. The collected data was analyzed using SPSS version 21.00 for the window. Results: Of 280 HCPs to whom the questionnaire initially administered, 213 respondents filled and returned the questionnaire, giving a response rate of 76.1%, and were included in the analysis. The study revealed that 78.9% and 47.9% of HCPs have poor knowledge and negative attitude towards ADR reporting respectively. Among respondents, 38% of HCPs encountered patient with ADR, 90.2% of them reported the ADR they encountered, of them only 10.8% were reported to Ethiopian food, medicine, and healthcare administration and control authority, a regulatory body for receiving and monitoring ADR throughout the country. Conclusion: HCPs in TASH had poor knowledge, attitude and practice towards ADRs reporting. The hospital should devise strategies to enhance detection and reporting of ADRs.