The COVID-19 disease burden continues to be high worldwide and vaccines continue to be developed to help combat the pandemic. Acceptance and risk perception for COVID-19 vaccines is unknown in Botswana despite the government's decision to roll out the vaccine nationally. Objectives This study aims to assess the acceptance rate and risk perception of COVID-19 vaccines amongst the general population in Botswana. Methods We interviewed 5300 adults in Botswana from 1-28 February 2021 using self-administered questionnaires. The main outcomes of the study were vaccine acceptance and hesitancy rates. Demographic, experiential and socio-cultural factors were explored for their association with outcome variables. Results Two-thirds of the participants were females (3199), with those aged 24-54 making the highest proportion (61%). The acceptance rate of COVID-19 vaccine was 73.4% (95% CI: 72.2%-74.6%) with vaccine hesitancy at 31.3% (95% CI: 30.0%-32.6%). When the dependent variable was vaccine acceptance, males had higher odds of accepting the vaccine compared to females (OR = 1.2, 95% CI: 1.0, 1.4). Individuals aged 55-64 had high odds of accepting the vaccine compared to those aged 65 and above (OR = 1.2, 95% CI: 0.6, 2.5). The odds of accepting the vaccine for someone with primary school education were about 2.5 times that of an individual with post graduate level of education. Finally, individuals with comorbidities had higher odds (OR = 1.2, 95% CI: 1.0, 1.5) of accepting the vaccine compared to those without any underlying conditions. Conclusion This study demonstrated a high acceptance rate for the COVID-19 vaccine and a low risk perception in Botswana. In order to achieve a high vaccine coverage and ensure a successful vaccination process, there is need to target populations with high vaccine hesitancy rates. A qualitative study to assess the factors associated with vaccine acceptance and hesitancy is recommended to provide an in-depth analysis of the findings.