The past two decades have seen an accumulation of theoretical and empirical evidence for the interlinkages between human health and well-being, biodiversity and ecosystem services, and agriculture. The COVID-19 pandemic has highlighted the devastating impacts that an emerging pathogen, of animal origin, can have on human societies and economies. A number of scholars have called for the wider adoption of One Health integrated approaches to better prevent, and respond to, the threats of emerging zoonotic diseases. However, there are theoretical and practical challenges that have precluded the full development and practical implementation of this approach. Whilst integrated approaches to health are increasingly adopting a social-ecological system framework (SES), the lack of clarity in framing the key concept of resilience in health contexts remains a major barrier to its implementation by scientists and practitioners. We propose an operational framework, based on a transdisciplinary definition of Socio-Ecological System Health (SESH) that explicitly links health and ecosystem management with the resilience of SES, and the adaptive capacity of the actors and agents within SES, to prevent and cope with emerging health and environmental risks. We focus on agricultural transitions that play a critical role in disease emergence and biodiversity conservation, to illustrate the proposed participatory framework to frame and co-design SESH interventions. Finally, we highlight critical changes that are needed from researchers, policy makers and donors, in order to engage communities and other stakeholders involved in the management of their own health and that of the underpinning ecosystems.