An evaluation of emerging issues in One Health (OH) in Sub-Saharan Africa was undertaken to map the existing OH initiatives in Sub-Saharan African (SSA) countries. Desk review, expert opinions survey, limited interviews and wider consultations with selected OH stakeholders were conducted. The strengths, weaknesses, opportunities and threats to OH initiatives were identified. OH influence, interest and impacts were evaluated. One Health is transiting from multidisciplinary to transdisciplinary concepts and OH viewpoint should move from ‘proxy for zoonoses’, to include issues of climate change, nutrition and food safety, social sciences, geography, policy and planning, economics, welfare and well-being, antimicrobial resistance (AMR), vector-borne diseases, toxicosis and pesticides issues. While the identified major strengths should be boosted, the weaknesses should be addressed.OH Networks in SSA were spatially and temporally spread across SSA and stakeholders were classified as key, latent, marginal and OH defenders. Imbalance in stakeholders’ representation led to hesitation in buying-in from stakeholders who are outside the main networks. Theory of change, monitoring and evaluation frameworks, and tools to standardized evaluation of OH policies is needed for sustained future of OH and the future OH engagement should be outputs and outcomes-driven and not activity-driven.National roadmap for OH implementation and institutionalization is necessary and proofs of concepts in OH should be verified and scaled-up. Dependence on external funding is unsustainable and must be addressed. Necessary policy and legal instrument to support OH nationally and sub-nationally should be implemented taking cognizance of contemporary issues like urbanization, endemic poverty and other emerging issues. Utilizing current technologies and OH approach to address ongoing pandemic of COVID-19 and other emerging diseases is desirable. Finally, OH implementation should be anticipatory and not reactive to significantly benefit budgeting and contain disease outbreaks in animal sources before the risk of spillover to human can be envisaged.