<p><strong>Background:</strong> Corona virus disease-2019 (COVID-19) is a family of severe acute respiratory infection first detected in 2019 in China. It has made high morbidity and mortality across the world. Currently, most countries including Ethiopia have taken preventive measures including vaccine. However, there is still limited evidence in COVID-19 vaccine acceptability and perceived barriers among some subgroups like university students. Therefore, this study was aimed to assess it and fill the information gap to enable intervention.</p><p><strong>Methods:</strong> A cross-sectional study was conducted from April 01 to 30 2022 at Dire Dawa university and 337 students were selected using simple random sampling technique. Data was collected using structured, self-administered questionnaire, entered and cleaned by Epi DATA (Version 3.1) and analyzed using SPSS (Version 22). A p&lt;0.2 at Bivarate to select variables for multivariable and &lt;0.05 at multivariable with 95% CI was considered as statistical significance.  </p><p><strong>Results:</strong> COVID-19 vaccine acceptance was 26.7% (95% CI: 22-31.5%). Urban resident (AOR: 3.13, CI: 1.61-6.10), mothers’ education (AOR: 3.48, CI: 1.44-8.43), knowledge (AOR: 2.23, CI: 1.21-4.11) and favorable intention towards COVID-19 prevention (AOR: 2.21, CI: 1.11-4.38) were independent factors associated with COVID-19 vaccine acceptance.</p><p><strong>Conclusions:</strong> COVID-19 vaccine acceptance was lower than national average in Ethiopia. The predictors were residence, mothers’ education, knowledge and intention towards COVID-19 prevention. Major barriers were misconceptions, uncertainty on effectiveness, concern on side effects and a need to know more about the vaccine. Integrated health education campaign on vaccine’s misconception was recommended. </p>