Background: Coronavirus 2019 (COVID-19) is currently a global health threat and an international public health emergency. As of 21 January 2021, 97.8 million cases with more than two million deaths were recorded worldwide while in Ethiopia 132,326 confirmed cases and 2057 deaths were reported. Hence, the aim of the present study was to determine the magnitude of knowledge, attitude, and practice toward COVID-19 among the population who visited the health center for COVID-19 screening. Methods: A health institution-based cross-sectional study was conducted among the 384 study population visiting Dessie health center for COVID-19 screening from September 1, to October 21, 2020 using a simple random sampling technique. A structured questionnaire was used to obtain information related to sociodemographic characteristics, Knowledge (eleven questions), attitude (six questions) and practice (nin questions). Both bivariable and multi-variable logistic regression analyses with a 95% confidence interval were used to identify factors associated with poor knowledge and practice. A P-value of <0.05 was considered statistically significant. Results: Out of the total study participants 61.5% were males, 52.6% of them were aged between 30 and 49 years and 85.2% of them were living in urban areas. The magnitude of poor knowledge and poor practice was 187 (48.7%) and 160 (41.7%), respectively. Poor knowledge had statistically significant association with Illiteracy (AOR= 5.53, 95%CI= 1.03-29.68, P= 0.046) and having no contact history (AOR=0.39, 95%CI=0.21–0.73, P=0.003). Statistically significant association existed between poor practice and parameters which addressed educational status, travel history, and poor knowledge level of study participants. Conclusion: Alarmingly high poor knowledge, negatively skewed attitude, and poor practice regarding the COVID-19 pandemic was indicated. Therefore, health education programs aimed at mobilizing and improving COVID-19-related knowledge, attitude, and practice are urgently needed, especially for those who are illiterate, having travel and contact history, or generally among underprivileged populations.