Background: In 2021 the South African government launched a large COVID-19 immunization campaign with the goal of reaching more than 40 million individuals. Nonetheless, certain international largely internet-based surveys at the time showed a significant proportion of vaccine hesitancy in South Africa. This study aims to determine and co-create with local stakeholders a comprehensive understanding of vaccine hesitancy and opportunities to support the promotion of other COVID-19 health-promoting behaviours at community level. Methods: A mixed-methods multiple case-study design; informed by the socio-ecological model of behaviour change. Four socio-economically diverse communities across South Africa will be selected and data collection will take place concurrently through three iterative phases. Phase 1 will provide insights into community experiences of COVID-19 (response) through desktop mapping exercises, observations, in-depth interviews, and focus group discussions (FGDs) designed as expression sessions with local stakeholders. Phase 2 will explore the extent and drivers of community acceptance of COVID-19 vaccines. This phase will comprise a survey based on WHO’s Behavioural and Social Drivers of Vaccination tool as well as further FGDs with community members. Phase 3 will involve cross-case study syntheses and presentation of findings to national role-players. Discussion: This study will provide ground up, locally responsive, and timeous evidence on the factors influencing COVID-19 health-seeking behaviours to inform ongoing management and mitigation of COVID-19 in South Africa. It will also provide insights into the applicability of a novel vaccine hesitancy model in Africa.