AimThis study aimed at assessing COVID-19 vaccine hesitancy, adverse events after immunization, and associated factors among the general population during the early phase of the COVID-19 vaccination program in Ethiopia.Subject and methodsWe conducted a national online survey of 853 persons among the Ethiopian general population between June 19 and July 31, 2021, in three languages that included Amharic, Afan Oromo, and English. Responses obtained from Google Forms were downloaded in Excel format and then filtered, coded, exported, and analyzed using the Statistical Package for Social Sciences (SPSS) version 26. Binary logistic regression was employed to identify factors associated with the outcome variables, and p < 0.05 was used as the cutoff point to declare the significance association. This study was approved by the Ethical Review Committee of the School of Pharmacy, College of Health Sciences, Addis Ababa, Ethiopia (ERB/290/13/2021).ResultsOf the 853 study participants, the majority were male (57.4%), and their mean (& PLUSMN;SD) age was 32.0 (& PLUSMN;13.57) years. More than half, namely 61.0% (95% CI: 57.1%-64.8%) were hesitant to take the COVID-19 vaccine. Fear of side effects (21.3%) and doubts about its effectiveness (16.9%) were their main reasons for not receiving the vaccine. Of the 214 participants who received the first dose of the COVID-19 vaccine, 34.6% were hesitant to get it. The overall mean score (& PLUSMN;SD) of the attitude of the participants toward COVID-19 and its vaccine was 31.21 (& PLUSMN;3.21) from an overall score of 45, with 53.6% scoring below the mean and having a poor attitude toward COVID-19. Among the 145 (67.8%) participants that experienced adverse events following immunization (AEFI) with the COVID-19 vaccine, the most common were pain at the injection site (52.4%), headache (40.7%), and fatigue (35.2%). The odds of vaccine hesitancy were reduced by 57% and 93% among participants with good attitudes toward the COVID-19 vaccine (AOR: 0.43; 95% CI: 0.29-0.65) and those who recommended the vaccine to other people (AOR: 0.07; 95% CI: 0.04-0.12), respectively. The odds of COVID-19 vaccine side effects were reduced by 57% and 69% among participants in the age group of 30-39 years (AOR: 0.43; 95% CI: 0.19-0.98) and 40-49 years (AOR: 0.31; 95% CI: 0.12-0.86), respectively, when compared to those in the age group of 18-29 years.ConclusionHesitancy to first and second doses of the COVID-19 vaccine was high among the general population in Ethiopia. Fear of adverse effects and doubts about its effectiveness were the most frequent reasons for not receiving the COVID-19 vaccine. More than half of the participants had a poor attitude toward COVID-19 and its vaccine. More than two thirds of vaccinated participants experienced one or more AEFIs with COVID-19 vaccine administration.