The coronavirus disease 2019 (COVID-19) pandemic resulted in the closure of schools to slow the spread of the virus across populations, and the administration of vaccines to protect people from severe disease, including school children and adolescents. In Zambia, there is currently little information on the acceptance of COVID-19 vaccines among school-going children and adolescents despite their inclusion in the vaccination programme. This study assessed the knowledge, attitudes, and acceptance of COVID-19 vaccines among secondary school pupils in Lusaka, Zambia. A cross-sectional study was conducted from August 2022 to October 2022. Of the 998 participants, 646 (64.7%) were female, and 127 (12.7%) would accept to be vaccinated. Those who were willing to be vaccinated had better knowledge (68.5% vs. 56.3%) and a positive attitude (79.1% vs. 33.7%) compared to those who were hesitant. Overall, the odds of vaccine acceptance were higher among pupils who had higher knowledge scores (AOR = 11.75, 95% CI: 6.51-21.2), positive attitude scores (AOR = 9.85, 95% CI: 4.35-22.2), and those who knew a friend or relative who had died from COVID-19 (AOR = 3.27, 95% CI: 2.14-5.09). The low vaccine acceptance among pupils is of public health concern, emphasising the need for heightened sensitisation programmes that promote vaccine acceptance among pupils in Zambia.