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The current healthcare system's efforts to reduce the spread of COVID-19 in Ethiopia and limit its effects on human lives are being hampered by hesitancy toward the COVID-19 vaccine. The aim of this study was to assess the knowledge levels, attitudes, and prevention practices of COVID-19, in the context of the level of vaccine hesitancy with other associated factors in Ethiopia. A community-based cross-sectional design with mixed-method data sources was employed. It comprised 1361 study participants for the quantitative survey, with randomly selected study participants from the studied community. This was triangulated by a purposively selected sample of 47 key informant interviews and 12 focus group discussions. The study showed that 53.9%, 55.3%, and 44.5% of participants had comprehensive knowledge, attitudes, and practices regarding COVID-19 prevention and control, respectively. Similarly, 53.9% and 47.1% of study participants had adequate knowledge and favorable attitudes toward the COVID-19 vaccine. Only 29.0% of the total survey participants had been vaccinated with at least one dose of vaccine. Of the total study participants, 64.4% were hesitant about receiving the COVID-19 vaccination. The most frequently reported reasons were a lack of trust in the vaccine (21%), doubts regarding the long-term side effects (18.1%), and refusal on religious grounds (13.6%). After adjusting for other confounding factors, geographical living arrangements, the practices of COVID-19 prevention methods, attitudes about the vaccine, vaccination status, perceived community benefit, perceived barriers toward vaccination, and self-efficacy about receiving the vaccine were significantly associated with vaccine hesitancy. Therefore, to improve vaccine coverage and reduce this high level of hesitancy, there should be specifically designed, culturally tailored health education materials and a high level of engagement from politicians, religious leaders, and other community members.
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