Many intrinsically related determinants of health and disease exist, including social and economic status, education, employment, housing, and physical and environmental exposures. These factors interact to cumulatively affect health and disease burden of individuals and populations, and to establish health inequities and disparities across and within countries. Biomedical models of health care decrease adverse consequences of disease, but are not enough to effectively improve individual and population health and advance health equity. Social determinants of health are especially important in Latin American countries, which are characterised by adverse colonial legacies, tremendous social injustice, huge socioeconomic disparities, and wide health inequities. Poverty and inequality worsened substantially in the 1980s, 1990s, and early 2000s in these countries. Many Latin American countries have introduced public policies that integrate health, social, and economic actions, and have sought to develop health systems that incorporate multisectoral interventions when introducing universal health coverage to improve health and its upstream determinants. We present case studies from four Latin American countries to show the design and implementation of health programmes underpinned by intersectoral action and social participation that have reached national scale to effectively address social determinants of health, improve health outcomes, and reduce health inequities. Investment in managerial and political capacity, strong political and managerial commitment, and state programmes, not just time-limited government actions, have been crucial in underpinning the success of these policies.