Background: COVID-19 is a highly contagious disease and a pandemic. Knowledge, attitude, and practice of people about this disease can play an essential role in better accepting executive actions set by health officials and national planners. Objectives: This study aimed to determine the level of knowledge, attitude, and practice of the general population of South Khorasan province about COVID-19 and the influencing factors. Methods: This cross-sectional study was performed online on 699 people living in South Khorasan, Iran. The participants were chosen by a convenience sampling technique. The research tool was an adapted questionnaire from researchers that included demographic characteristics, 15 questions on awareness, 12 questions on attitude, and seven questions on practice. Data were analyzed using the independent t test, one-way analysis of variance, and Pearson correlation coefficient. Results: The levels of knowledge, attitude, and practice of the participants were 73.13, 80, and 84.85%, respectively. The most common symptoms of this disease were shortness of breath, dry cough, and fever or headache, in sequence. More than half of the participants (56.90%) felt at risk for contracting the disease. Most participants washed their hands (80%) and used a facemask (79.60%). The correlation between awareness and practice was 0.60. Older, divorced, and low-educated people had lower knowledge and practice. Conclusions: Despite that the levels of knowledge, attitude, and practice of people was good regarding COVID-19 in this study, the continuous informing of the people through television, radio, and social media is needed for maintaining the status quo. Besides, new approaches and policies for the poor, rural populations, the elderly, the illiterate, and the unemployed should be adopted by relevant authorities due to their lower level of knowledge and practice.