Effective spontaneous AEFI reporting is the first step to ensuring vaccine safety. Half of the global population lives in countries with weak vaccine safety monitoring systems, especially in the African, Eastern Mediterranean, and Western Pacific regions. Further, Immunisation services have been upscaled without commensurate effective AEFI surveillance systems. Hence, this study aims to comprehensively investigate the impediments to an effective AEFI surveillance system. Given the programmatic and regulatory implications, understanding these impediments would facilitate the development and implementation of policies and strategies to strengthen the AEFI surveillance system in Nigeria. A qualitative research design (using a grounded theory approach) was employed by conducting ten key informant interviews and two Focus Group Discussion sessions among the study population to identify the barriers impeding optimal AEFI surveillance and documentation in Nigeria. This study found that the AEFI surveillance system is in place in Nigeria. However, its functionality is sub-optimal, and the potential capacity is yet to be fully harnessed due to health systems and socio-ecological impediments. The identified impediments are human-resource-related issues- knowledge gaps; limited training; lack of designated officers for AEFI; excessive workload; poor supportive supervision and attitudinal issues; caregiver’s factor; governance and leadership- moribund AEFI committee; lack of quality supervisory visit and oversight and weak implementation of AEFI policy guidance. Others include funding and logistics issues- no dedicated budget provision and weak referral mechanism; insecurity; socio-economic and infrastructural deficits- poverty, geographical barriers, limited ICT skills, and infrastructure; and poor feedback and weak community engagement by the health workers. Findings from this study provide empirical evidence and serve as an advocacy tool for vaccine pharmacovigilance strengthening in Nigeria. Addressing the impediments requires health system strengthening and a whole-of-the-society approach to improve vaccine safety surveillance, restore public confidence and promote vaccine demand, strengthen PHC services, and contribute to attaining UHC and SDGs.