Policymakers across countries promote cross-sector collaboration as a route to improving population health. Yet little is known about the impact of cross-sector collaboration on health and health equity. In England, major health system reforms in 2022 established 42 Integrated Care Systems (ICSs)—area-based partnerships between health care, social care, public health, and other sectors—to plan and coordinate services. ICSs have been given explicit policy objectives to reduce health inequalities. The research uses a mix of methods to understand how local NHS organizations are collaborating with other sectors to reduce health inequalities under the latest health system reforms in England. The research involved three phases. First was an umbrella review to synthesize a large body of international evidence on the health impacts of collaboration between local health care and non-health care organizations, and the factors shaping how these partnerships function. Second was analysis of the policy context, development, aims, structure, and characteristics of England’s new ICSs—including in-depth analysis of national policy on reducing health inequalities in England through the new systems. Phase two also included analysis of how ICSs fit with previous national policies on cross-sector collaboration to improve health and reduce health inequalities in England since 1997. Third was qualitative analysis of how local NHS, social care, public health, and other organizations are collaborating within ICSs to reduce health inequalities, based on in-depth interviews with senior leaders in three more socioeconomically deprived ICSs in England. A framework based on the initial evidence synthesis and broader literature on public policy implementation are used to analyse the data. Overall, there is little convincing evidence to suggest that collaboration between local health care and non-health care organizations improves health or health equity. Local collaborations should be understood in their broader political and economic context, and as one component within a wider system of factors interacting to shape health and health inequalities. The role of national policy context and political choices is frequently underplayed. Local leaders in England’s new ICSs described strong commitment to working together to reduce health inequalities, but faced a combination of conceptual, cultural, capacity, and other challenges in doing so. A mix of factors shaped local collaboration—from how national policy aims are defined and understood, to the resources and relationships among local organizations to deliver them. These factors interact and have varying influence. The national policy context played a dominant role in shaping local collaboration experiences—frequently making it harder not easier. Closer alignment between policy aims, processes, and resources to reduce health inequalities is likely needed to avoid policy failure as ICSs evolve. The findings point to implications for policy and research on cross-sector collaboration to reduce health inequalities in the UK and internationally.