Background: Primary care nurses, including nurse practitioners (NPs), registered nurses (RNs), and licensed practical nurses/registered practical nurses (LPNs/RPNs), play a pivotal role in pandemic management and outbreak planning. There is extensive literature surrounding COVID-19 vaccination efforts in Canada; however, limited research addresses the involvement of primary care nurses, as well as the organization and integration of these efforts into primary care settings. This study aimed to describe the organizational challenges, barriers, and facilitators to primary care nurses’ roles in COVID-19 vaccination. Methods: As part of a mixed methods case study, we conducted semi-structured qualitative interviews with primary care nurses employed in regions across four Canadian provinces: British Columbia, Ontario, Nova Scotia, and Newfoundland and Labrador. During the interviews, nurses described their activities throughout different phases of the COVID-19 pandemic, factors that facilitated or impeded their efforts, and potential contributions nurses could have made. We applied a thematic analysis approach and analyzed codes related to the organization of the COVID-19 vaccination rollout. Results: We interviewed 76 nurses (24 NPs, 37 RNs, and 15 LPNs/RPNs) between May 2022 and January 2023. We identified five overarching components of the COVID-19 vaccination rollout that influenced primary care nurses’ perceptions and experiences: (1) information, (2) training, (3) coordination, (4) integration, and (5) compensation. Participants reported both positive and negative experiences with the vaccine rollout. Rapidly evolving information made it difficult for nurses to stay informed and training for vaccine delivery posed barriers due to time requirements and redundancy. Support was often lacking for new electronic systems, and regional coordination varied, sometimes resulting in miscommunication. Delays in integrating vaccination into primary care, logistical challenges, and disparities in compensation between nurses and physicians also presented challenges. Conclusions: Findings highlight the critical roles of primary care nurses in mass vaccination campaigns, underscoring the need for targeted information, effective training, streamlined coordination, better integration into primary care, and more equitable compensation. Integrating these services into primary care can enhance future vaccination efforts by leveraging nurses’ expertise to improve vaccine access and delivery.