Community-based disease surveillance (CBS) is the backbone of the disease surveillance system in Ghana. The activities of Community-based Disease Surveillance Volunteers (CBSVs) in the Central Region have had a positive impact on the health of community members. However, little is known about the Surveillance System Structures (SSSs) and the CBSVs' knowledge levels on the various priority diseases and events. We used a cross-sectional descriptive survey to ascertain the status of SSSs and the knowledge level of CBSVs on priority diseases in the Central Region of Ghana. An ethical clearance was sought from the University of Cape Coast and Ghana Health Service. A sample of 1, 381 communities were systematically sampled from 2,232 communities for this study. A structured questionnaire was used to collect data from the CBSVs within 12 weeks and was analyzed using Statistical Package for Social Sciences (SPSS). The results show that (35%) of the communities have no CBSVs, 48% have no registers, and 40% have not submitted any report for the past 1 year. Generally, (54%) of the CBSVs have low knowledge about priority diseases and events compared with the recommended national standards of 80% or more. Based on the findings of the study it could be concluded that there are weak community-based surveillance system structures and low CBSV knowledge of priority diseases and events in some communities in the Central Region of Ghana which could put the region at a higher risk of recording outbreaks that can result to morbidities, deformities and mortalities. This study recommends a multi-sectorial approach to ensure effective implementation of the Community-Based Surveillance (CBS) system. Stakeholders such as UNICEF, WHO, CDC, GHS MMDAs, and community members should collaborate to ensure improved recruitment, reporting systems, training, supervision, and provision of incentives for CBSVs to strengthen the CBS system and prevent outbreaks.