Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was characterized as the etiology for a cluster of pneumonia cases that spread rapidly, causing considerable morbidity and mortality worldwide. By April 2021, more than 2,996,791 deaths were reported globally. Proper updated infection control protocol for Coronavirus disease 2019 (COVID-19) must be provided to every health care facility. Objectives: To evaluate the knowledge, attitude, perception of barriers, and practices among Egyptian health care workers (HCWs) regarding COVID-19 disease. Methodology: A cross-sectional study using an online questionnaire through a link shared on social networking sites was conducted on 480 HCWs from different regions in Egypt. Results: This assessment included a sample of 480 HCWs. The total knowledge score was (19.95±2.4). Satisfactory knowledge was reported among 60%. Total attitude score was (18.1±3.7) with positive attitude being reported among 23.3%. Total practice score was (10.6±1.1) and good practice was reported among 89.2%. Conclusion: There were satisfactory knowledge and practice with a low positive attitude regarding COVID-19 which requires more efforts to improve precautionary measures and training programs in hospitals.