Vaccine hesitancy has emerged as a significant global challenge impacting healthcare institutions, workplaces and governments alike. Despite concerted efforts by the government and numerous other institutions in South Africa, low vaccination rates persist (33% as of November 13, 2023), reflecting the persistence of this global challenge. This challenge is particularly pronounced in educational institutions such as institutions of higher learning in South Africa, where many people converge, increasing the risk of viral exposure. This study aims to assess the knowledge, attitudes, and perceptions of healthcare workers (HCWs) at a Nursing College regarding voluntary and mandatory COVID-19 vaccination. Employing a quantitative approach, a survey with closed-ended Likert-type questions was administered to 504 individuals at the College. The sample size of 218 respondents was calculated based on a margin of error of 5%, a confidence level of 95%, and an additional 25% contingency for potential incomplete data, resulting in a final representative sample of 270 respondents. The Statistical Package for Social Sciences (SPSS) was used for the analysis. Findings indicate a high uptake of voluntary COVID-19 vaccinations among HCWs, with some being mandated. Most HCWs demonstrated a strong commitment to safeguarding themselves and others. Despite concerns, HCWs thought the COVID-19 vaccines were effective, and their views were supported by a low level of infection among the participants, underscoring its efficacy in preventing transmission. Effective communication emerged as a critical factor in addressing post-vaccination behaviours and enhancing vaccine acceptance. However, the findings also highlighted the need for tailored outreach strategies to specific audiences, such as pregnant women, and the importance of addressing concerns about adverse effects through clear and open communication. Several factors influencing the choice between mandatory and voluntary vaccination were identified, including eligibility concerns, religious convictions, and financial considerations. Notably, concerns about safety and knowledge gaps outweighed these factors, suggesting the need for targeted educational initiatives to bolster vaccine acceptance. In conclusion, this study provides valuable insights into the dynamics of vaccination acceptance among an influential occupational group, with implications for the acceptance of other vaccines. Vaccination efforts can be strengthened by addressing concerns, enhancing communication strategies, and tailoring outreach efforts to promote public health in light of future outbreaks.Author summaryConception and design of the study: LM, TSData acquisition: LMData analysis: LMInterpretation of the data: LM, TSDrafting of the paper: LMCritical revision of the paper: TSBoth authors approved the final manuscript