This study examined the support for vaccine mandates and uptake among clinical and non-clinical staff at a tertiary hospital in northern Nigeria, focusing on variation of survey responses based on job position, socio-demographic characteristics, and perceived risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Using an explanatory, sequential, mixed-methods design and deploying a pragmatic paradigm, 370 healthcare workers were administered structured questionnaires. This was followed by in-depth interviews with a sub-sample of respondents to further clarify the responses regarding support for the coronavirus disease 2019 (COVID-19) vaccine mandate. Findings demonstrated that less than one-half of respondents supported the COVID-19 mandate, and only one in three had received the recommended COVID-19 vaccine doses. Support for the vaccine mandate and vaccine uptake were predicted by profession, work experience, number of children, health status, and risk perception. Support for the vaccine mandate was ascribed to ethical and professional duty, whereas opposition was associated with respect for autonomy and human rights. This study documents the need to enhance support for vaccine mandates and uptake among healthcare workers through sustainable strategies, as Nigeria's healthcare workers are considered a source of trust and role models for the rest of society.