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Abstract The promise of COVID-19 vaccines in ending the pandemic can only be achieved by overcoming the challenge of vaccine refusal. Healthcare workers (HCWs) are the trusted advisors of vaccination decisions. Recommendations for vaccinating children against COVID-19 are recently gaining more public health attention due to the role of children in disease transmission and associated morbidities. Vaccination is one of the first medical decisions parents or guardians make on behalf of their children. To investigate the determinants associated with vaccine acceptability among the general population through a direct interview questionnaire and assess guardians’ views towards childhood COVID-19 vaccinations. This cross-sectional study included 2919 participants A pre-designed structured questionnaire about COVID-19 vaccination acceptability was completed by trained interviewers and interviewing the participants or their guardians (for those below 18 years old). Nearly two-thirds of participants (66.5%) accepted vaccination, 20.2% were refusing and 13.3% were hesitant. Most participants who were guardians of children below 12 years and from 13 to 17 years reported that they would accept vaccination of their children (72.5% and 70.5%, respectively). The acceptance rate among HCWs was 58.2%. The main reasons beyond vaccine refusal were mistrust of vaccine efficacy (39.5%) and having concerns regarding vaccine safety (38.8%). In a multivariable regression model, being male (OR 1.362, 95% CI 1.082–1.714, p = 0.008) resident in rural area (OR 1.796, 95% CI 1.435–2.247, p = 0.000), and lower education (OR 1.245, 95% CI 1.018–1.523, p = 0.033) were associated with an increased acceptance to be vaccinated. The acceptance rate for vaccinating children reported among their guardians was higher than adults for themselves. Extremes of age showed higher vaccine acceptance compared to young adults. Upper Egypt governorates (Faiyum and Giza) were outpacing Lower Egypt governorates in vaccination acceptance rates.