BACKGROUND: Policymakers in many countries promote collaboration between health care organizations and other sectors as a route to improving population health. Local collaborations have been developed for decades. Yet little is known about the impact of cross-sector collaboration on health and health equity. METHODS: We carried out a systematic review of reviews to synthesize evidence on the health impacts of collaboration between local health care and non-health care organizations, and to understand the factors affecting how these partnerships functioned. We searched four databases and included 36 studies (reviews) in our review. We extracted data from these studies and used Nvivo 12 to help categorize the data. We assessed risk of bias in the studies using standardized tools. We used a narrative approach to synthesizing and reporting the data. RESULTS: The 36 studies we reviewed included evidence on varying forms of collaboration in diverse contexts. Some studies included data on collaborations with broad population health goals, such as preventing disease and reducing health inequalities. Others focused on collaborations with a narrower focus, such as better integration between health care and social services. Overall, there is little convincing evidence to suggest that collaboration between local health care and non-health care organizations improves health outcomes. Evidence of impact on health services is mixed. And evidence of impact on resource use and spending are limited and mixed. Despite this, many studies report on factors associated with better or worse collaboration. We grouped these into five domains: motivation and purpose, relationships and cultures, resources and capabilities, governance and leadership, and external factors. But data linking factors in these domains to collaboration outcomes is sparse. CONCLUSIONS: In theory, collaboration between local health care and non-health care organizations might contribute to better population health. But we know little about which kinds of collaborations work, for whom, and in what contexts. The benefits of collaboration may be hard to deliver, hard to measure, and overestimated by policymakers. Ultimately, local collaborations should be understood within their macro-level political and economic context, and as one component within a wider system of factors and interventions interacting to shape population health.