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