Background Adverse drug reactions (ADRs) are major health problems which are of global concern. Spontaneous reporting of adverse drug reactions constitutes a crucial contribution to patient care. Objective The purpose of this study was to assess the knowledge, attitudes, and practices of healthcare professionals towards adverse drug reaction reporting. Setting Health care professionals in Gondar, Ethiopia. Methods A cross-sectional study was conducted from March to May 2017. Data were collected through self-administered questionnaires. The collected data were analyzed using SPSS version 20. Binary logistic regression analysis was performed to distinguish factors that affect adverse drug reaction reporting. A p value < 0.05 was considered as a statistically significant. Main outcome measure Factors affecting adverse drug reaction reporting of health care professionals. Results Of 102 healthcare professionals included in this study, 61 (59. 8%) were nurses, 16 (15.7%) health officers, and 25 (24.5%) pharmacy professionals. Nearly 48 (47%) study participants had an inadequate level of knowledge towards adverse drug reaction reporting. The majority of participants 88 (86.3%) had a positive attitude, while more than half (51%) of study participants did not report the adverse drug reaction they encountered. Participants who had not taken adverse drug reaction reporting training (p = 0.037), health officers (p = 0.019), and nurse professionals (p = 0.001) showed a statistically significant association with an inadequate level of knowledge. Conclusion Even though the majority of healthcare professionals had a positive attitude, they had an inadequate level of knowledge and practice towards adverse drug reaction reporting.