BackgroundKnowledge and attitudes are among the key drivers of social behavioral change. We assessed employed health professionals' (HPs) knowledge, attitude, and practice regarding COVID-19 in Dessie city, northeast Ethiopia.MethodsA facility-based cross-sectional study was conducted among 419 HPs working at Dessie city from 17 to 21 May 2020. The data were collected using a self-administered structured questionnaire. Knowledge, attitude, and practice are measured using 19, 16, and 8 questions, respectively. Knowledge and attitude scores are dichotomized at the 3rd quartile, while practice is using the mean value. Data entry and analysis were conducted using EpiData Manager 4.2 and SPSS 25, respectively. Three independent logistic regression analyses were carried out to determine the associated factors. We defined significant association at a p-value of < 0.05.ResultsOut of 419 participants, 369 (88.1%) have sufficient knowledge regarding COVID-19 (95% CI: 85–91). The mean knowledge score is 16.8 with a ± 2.1 SD. Similarly, 355 (84.7%) of the HPs have a favorable attitude toward COVID-19 (95% CI: 81–87.9). The mean attitude score is 14 with ± 2.1 SD. However, practice regarding COVID-19 is adequate only in 69.7% (292) of the HPs (95% CI: 65.2–94). The mean practice score is 5.1 with a ± 1.3 SD. Sufficient knowledge is significantly associated with the type of health facility (AOR: 4.4, 95% CI: 1.4–13.3), degree and above education (AOR: 2.6, 95% Cl: 1.4–4.9), radio availability (AOR: 2.4, 95% CI: 1.3–4.7), and social media utilization (AOR: 2.3, 95% CI: 1.1–5.1). The predictors of favorable attitude are training (AOR: 3.1, 95% CI: 1.6–6.1), sufficient knowledge (AOR: 5.2, 95% Cl: 2.6–10.4), and type of health facility (AOR: 2.3, 95% CI: 1.1–5.2).ConclusionMost HPs have sufficient knowledge and a favorable attitude regarding COVID-19. However, practice is relatively low and there remains plenty to build assertive preventive behaviors. The gap between knowledge and practice should be narrowed through an appropriate social and behavioral change communication strategy.