Environmental and social determinants of health often co-occur, particularly among socially disadvantaged populations, yet because they are usually studied separately, their joint effects on health are likely underestimated. Building on converging bodies of literature, we delineate a conceptual framework to address these issues. Previous models provided a foundation for study in this area, and generated research pointing to additional important issues. These include a stronger focus on biobehavioral pathways, both positive and adverse health outcomes, and intergenerational effects. To accommodate the expanded set of issues, we put forward the Integrated Socio-Environmental Model of Health and Well-Being (ISEM), which examines how social and environmental factors combine and potentially interact, via multi-factorial pathways, to affect health and well-being over the life span. We then provide applied examples including the study of how food environments affect dietary behavior. The ISEM provides a comprehensive, theoretically informed framework to guide future research on the joint contribution of social and environmental factors to health and well-being across the life span.