Outbreaks of coral-eating crown-of-thorns starfish (COTS) pose a significant threat to the Great Barrier Reef (GBR) ecosystem and its associated industries. The COTS Control Program has become a core management action to protect coral and support socio-ecological health and resilience. It is the largest-scale intervention program on the GBR, with a fleet of vessels and trained crew managing starfish numbers to ecologically sustainable levels across approximately 200 reefs each year. The Program’s evolution and effectiveness hinge on the strength of the research partnerships that continue to drive innovation and inform its Integrated Pest Management approach, including strategic planning and tactical deployment of control effort. Here we provide an overview of the operations and outcomes of the Program, alongside the advances in research that underpin its efficacy and adaptive management. Over the past three years, the COTS Control Innovation Program (CCIP) has delivered more than 20 targeted research projects to further improve our ability to predict, detect and respond to these outbreaks. We provide a synthesis of the key findings and capabilities developed through this multi-disciplinary research program, including innovation in COTS biology/ecology, monitoring technologies, modelling, and decision-support tools. We reflect on key lessons learned and emerging opportunities for the future.