BackgroundIdentifying factors associated with vaccine uptake among health care workers (HCWs) remains crucial to generating evidence aimed at guiding national COVID-19 vaccination and future infectious disease outbreak strategies. This study aimed to elucidate these factors, focusing on the interplay between socio-demographic, health, knowledge, beliefs and attitudinal indicators. MethodsThis was a cross-sectional online survey administered to HCWs across South Africa between August and October 2022. Bivariate and Multivariate logistic regressions identified associations between COVID-19 vaccine uptake and demographics, occupational characteristics, general knowledge of and attitudes towards vaccination, perceived COVID-19 risk and perceived importance of COVID-19 vaccine attributes. ResultsAnalysis revealed high vaccine uptake rates among the sample of 5564 HCWs, with 87.6% of the sample vaccinated at the time of the study. Demographic measures significantly associated with vaccine uptake were age (P-value = 0.001), race (P-value = 0.021), religion (P-value = 0.004), and having a chronic illness (P-value <0.001). Belief and attitude measures significantly associated with vaccine uptake included: need for vaccines (P-value <0.001), perceived risk of infection (P-value = 0.001), perceived patient risk (P-value <0.001), and perceived vaccine knowledge (P-value <0.001). Multivariate analysis revealed that HCWs who listed their religion as African Spirituality (OR = 0.4; 95% CI = 0.2–0.7; P-value = 0.002) and had any occupation other than nurse or doctor (OR = 0.6; 95% CI = 0.4–0.8; P-value <0.001), were less likely to vaccinate, while HCWs who had a chronic condition (OR = 1.5; 95% CI = 1.2–2.0; P-value <0.001) were more likely to have been vaccinated. ConclusionThis study provides useful insights into the factors associated with and possibly driving COVID-19 vaccine uptake among HCWs in South Africa. These results add to a limited body of knowledge on contextual dynamics associated with vaccination programmes in Africa.