Background: There is increasing interest in using systems thinking to tackle ‘wicked’ policy problems in preventive health, but this can be challenging for policy-makers because the literature is amorphous and often highly theoretical. Little is known about how best to support health policy-makers to gain skills in understanding and applying systems thinking for policy action. Methods: In-depth interviews were conducted with 18 policy-makers who are participating in an Australian research collaboration that uses a systems approach. Our aim was to explore factors that support policy-makers to use systems approaches, and to identify any impacts of systems thinking on policy thinking or action, including the pathways through which these impacts occurred. Results: All 18 policy-makers agreed that systems thinking has merit but some questioned its practical policy utility. A small minority were confused about what systems thinking is or which approaches were being used in the collaboration. The majority were engaged with systems thinking and this group identified concrete impacts on their work. They reported using systems-focused research, ideas, tools and resources in policy work that were contributing to the development of practical methodologies for policy design, scaling up, implementation and evaluation; and to new prevention narratives. Importantly, systems thinking was helping some policy-makers to reconceptualise health problems and contexts, goals, potential policy solutions and methods. In short, they were changing how they think about preventive health. Conclusion: These results show that researchers and policy-makers can put systems thinking into action as part of a research collaboration, and that this can result in discernible impacts on policy processes. In this case, action-oriented collaboration and capacity development over a 5-year period facilitated mutual learning and practical application. This indicates that policy-makers can get substantial applied value from systems thinking when they are involved in extended co-production processes that target policy impact and are supported by responsive capacity strategies.