© 2020 The Author(s) Coronavirus disease 2019 (COVID-19) is not only a deadly disease outbreak but also affects the mental status of the population, including nurses. Nurses play a vital role in dealing with individuals with COVID-19. Nurses' infection control measures are affected by their knowledge, attitude, practice and psychological responses towards COVID-19. This study aimed to determine the knowledge, attitude, practice and psychological response among nurses toward the COVID-19 outbreak in northern Ethiopia. A hospital-based cross-sectional study design was employed. The data were collected from March to April 2020. Data were collected through a self-administered questionnaire. The data were entered into Epi-data manager version 4.2 and exported to SPSS v.23 for analysis. Descriptive analysis was reported to describe the demographic, mean knowledge, attitude practice and psychological response score of nurses. A total of 415 nurses participated in this study, resulting in a 100% response rate. Of the participants, 241 (58.1%) were female. Of the 415 nurses, 307 (74%), 278 (67%), 299 (72%) and 354 (85.3%) had good knowledge, good infection prevention practice, a favourable attitude and disturbed psychological response towards COVID-19, respectively.