Objectives: As of May 2023, over 500,000 COVID-19 cases and over 7,500 deaths have been reported in Ethiopia. Understanding community members' knowledge and perception of SARS-CoV-2 prevention is essential for directing public health interventions to reduce transmission and improve vaccination coverage. Here, we aimed to describe factors associated with knowledge of COVID-19 prevention among community residents in Eastern Ethiopia. Methods: We conducted a cross-sectional survey among a random sample of 880 participants in a Health and Demographic Surveillance System in the Harari Region, Ethiopia, from August to September 2021. Principal components analysis was used to create a score representing knowledge of COVID-19 prevention. Quasi-Poisson regression was used to examine associations between demographic characteristics and knowledge of COVID-19 prevention. Our survey also included information regarding knowledge of community or government measures to prevent COVID-19, healthcare services for children under five, and healthcare services for pregnant women. Results: The most cited individual measures to reduce the risk of contracting COVID-19 were washing hands with soap (91.5%) and wearing a facemask (89.2%), whereas least mentioned were avoiding domestic and international travel (22.2%) and wearing medical gloves (20.3%). The most recognized community or government measures to prevent SARS-CoV-2 transmission were closure of schools and universities (77.0%), advice to avoid gatherings (75.2%), and advice to stay home (62.3%). Adjusted analyses demonstrated that knowledge of COVID-19 prevention was higher among participants from rural areas than urban areas, those aged ≥65 years (<25 years as reference), with secondary education (no formal education as reference), with monthly income of ≥2,001 Birr (0-1,200 as reference), and were farmers or domestic/subsistence workers or government employees (unemployed as reference). Knowledge was lower among households with ≥5 household members (1-2 as reference). Of households with children under five and pregnant women, 9.4% and 12.3% missed at least one medical care visit since mid-March 2020 consequent to the pandemic, respectively. Conclusions: Public health interventions to reduce infectious disease transmission depend on perceptions of risk and knowledge. The survey found that most adults had good knowledge of methods for reducing risks of COVID-19, although knowledge differed between groups. A substantial number of respondents reported missing important healthcare visits. Understanding these factors may help Ethiopian authorities plan effective health education programs to control community and household transmission of SARS-CoV-2.