Higher education institutions (HEIs) developed and implemented a mandatory COVID-19 vaccination policy to facilitate vaccine acceptance and vaccination among universities' staff and students. However, little is known about influences of the mandatory vaccination policy on health science students at a university and they tend to result in vaccine hesitancy. To explore the influences of the mandatory COVID-19 vaccine policy on health sciences students' vaccine acceptance at HEIs in South Africa. The study was conducted in one of the universities in the Western Cape Province, South Africa. An interpretive qualitative exploratory-descriptive research was conducted with 10 participants who were selected using the purposive sampling method to participate in semi-structured interviews. Data were audio-recorded, transcribed verbatim and thematically analysed. Two themes and 12 sub-themes were identified during the data analysis, namely individual and group influencing factors, as well as contextual influencing factors. This study revealed that the COVID-19 vaccination mandatory policy influenced the students' quality of life, academic performance and well-being. The findings from this study indicate that there were perceived barriers related to personal and contextual influencing factors than benefits of COVID-19 vaccination. The understanding of and insight into the influences of the mandatory vaccination policy provided a basis for further strategies that may be developed to address COVID-19 vaccine infodemic, vaccine hesitancy and its risk effects. This can be done through collaboration with different stakeholders to educate health science students about the perceived benefits of COVID-19 vaccination.