Objectives: This study is aimed to assess factors associated with knowledge, attitude, and practice of COVID-19 among health care professional’s working in South Wollo Zone Hospitals, Northeast Ethiopia. Methods: Institution-based cross-sectional study was conducted among 422 health care professionals from 10 July to 10 August 2020, at the South Wollo Zone. A pre-tested self-administered structured questionnaire was used to collect the data. Both bi- and multi-variable logistic regressions were fitted to identify variables significantly associated with the outcome variables. Adjusted odds ratios with 95% confidence interval and p-value < 0.05 were used to determine significant factors. Results: About 92.4%, 64%, and 55% of the respondents had good knowledge, favorable attitude, and good practices toward corona virus disease, respectively. Being female (adjusted odds ratio = 0.23, confidence interval: 0.10, 0.56), age ⩾ 35 years (adjusted odds ratio = 0.14, confidence interval: 0.22, 0.84), being unmarried (adjusted odds ratio = 0.20, confidence interval: 0.70, 0.59), getting information from radio and television (adjusted odds ratio = 6.02, confidence interval: 2.09, 17.36), having average monthly income 93.55–163.67 USD (adjusted odds ratio = 8.00, confidence interval: 0.94, 33.10), and average monthly income > 163.70 USD (adjusted odds ratio = 11.41, confidence interval: 1.41, 15.23) were significantly associated with good knowledge about COVID-19. In addition, being unmarried (adjusted odds ratio = 0.70, confidence interval: 0.49, 0.97), having bachelor of science degree and above (adjusted odds ratio = 1.87, confidence interval: 2.24, 2.83), and getting information from seminars and workshops (adjusted odds ratio = 0.59, confidence interval: 0.35, 0.98) had association with good practice toward COVID-19 prevention and control method. Conclusion: More than 90% of the health care workers have good knowledge; nearly half of the respondents had unfavorable attitudes and poor practice toward COVID-19. The findings imply that the government and other stakeholders should implement further strategies for enhancing to change health care professional’s attitude and encourage to practice prevention and control methods.