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Adolescents and youths are a key part of the population that needs to be protected against the coronavirus disease 2019 (COVID-19). This is because they are more likely to spread the virus to vulnerable individuals. In view of these concerns, this study investigated the uptake of COVID-19 vaccines and associated factors among adolescents and youths attending secondary schools in Zambia. This cross-sectional study was conducted among 1500 school-going adolescents in Lusaka from September 2022 to November 2022. Overall, 1409 participants took part giving a response rate of 94%. Only 29.2% (n = 411) of the participants were vaccinated against COVID-19 at the time of the study. Compared to their unvaccinated counterparts, vaccinated adolescents and youths scored higher for knowledge (66.2% vs 57.8%) and attitudes (76.7% vs 39.4%) regarding COVID-19 vaccines. Healthcare workers, family/friends and social media were key sources of information regarding the vaccine. Factors associated with increased vaccine uptake were positive attitudes (AOR = 33.62, 95% CI: 19.92–56.73), indicating it was stressful to follow COVID-19 preventive measures (AOR = 1.47, 95% CI: 1.09–1.99), participants in Grade 12 (AOR = 3.39, 95% CI: 1.94–5.91), Grade 11 (AOR = 2.59, 95% CI: 1.94–5.91), Grade 10 (AOR = 3.48, 95% CI: 1.98–6.11) and Grade 9 (AOR = 3.04, 95% CI: 1.74–5.32) compared to Grade 8. This study found a relatively low uptake of COVID-19 vaccines among adolescents and youths in Zambia. There is a need to provide adequate strategies to address knowledge and attitude gaps regarding COVID-19 vaccines to improve …