Globally, gay, bisexual and other men who have sex with men (GBMSM) experience an increased burden of poor sexual, mental and physical health. Syndemics theory provides a framework to understand comorbidities and health among marginalised populations. Syndemics theory attempts to account for the social, environmental, and other structural contexts that are driving and/or sustaining simultaneous multiple negative health outcomes, but has been widely critiqued. In this paper, we conceptualise a new framework to counter syndemics by assessing the key theoretical mechanisms by which pathogenic social context variables relate to ill-health. Subsequently, we examine how salutogenic, assets-based approaches to health improvement could function among GBMSM across diverse national contexts. Comparative quantitative secondary analysis of data on syndemics and community assets are presented from two international, online, cross-sectional surveys of GBMSM (SMMASH2 in Scotland, Wales, Northern Ireland and the Republic of Ireland and Sex Now in Canada). Negative sexual, mental and physical health outcomes were clustered as hypothesised, providing evidence of the syndemic. We found that syndemic ill-health was associated with social isolation and the experience of stigma and discrimination, but this varied across national contexts. Moreover, while some of our measures of community assets appeared to have a protective effect on syndemic ill-health, others did not. These results present an important step forward in our understanding of syndemic ill-health and provide new insights into how to intervene to reduce it. They point to a theoretical mechanism through which salutogenic approaches to health improvement could function and provide new strategies for working with communities to understand the proposed processes of change that are required. To move forward, we suggest conceptualising syndemics within a complex adaptive systems model, which enables consideration of the development, sustainment and resilience to syndemics both within individuals and at the population-level.