Vaccine uptake in younger Australian women living in rural and regional communities is poorly understood. This research explored factors affecting their decision making in the context of social determinants of health. A mixed methods design applying an explanatory sequential approach commenced with an online questionnaire followed by in-depth interviews with a sample of the same participants. The majority (56%) of participants indicated a positive intention to be vaccinated against COVID-19, but a substantially high proportion (44%) were uncertain or had no intention to be vaccinated. Significant factors affecting vaccine uptake included inadequate and sometimes misleading information leading to poor perceptions of vaccine safety. The personal benefits of vaccination—such as reduced social restrictions and increased mobility—were perceived more positively than health benefits. Additionally, access issues created a structural barrier affecting uptake among those with positive or uncertain vaccination intentions. Understanding factors affecting vaccine uptake allows for more targeted, equitable and effective vaccination campaigns, essential given the importance of widespread COVID-19 vaccination coverage for public health. The population insights emerging from the study hold lessons and relevance for rural and female populations globally.