ObjectiveWe present the ‘COVID-19 evidence ecosystem’ (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises. Study Design and SettingBringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews, supporting evidence-based (living) guidelines, knowledge translation, detecting research gaps and deriving recommendations, backed by technical infrastructure and capacity building. ResultsCEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys’ late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency. ConclusionCEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter-)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network.