Health and development organizations continue to face obstacles in leadership and management as they work to scale their programs. The Challenge Initiative (TCI) faced this challenge in 2016 when it was first tasked to rapidly scale-up proven family planning interventions in more than 200 cities across 13 countries. To address this, TCI was thoughtfully designed as a global platform with a business-unusual model—supporting local governments in leading and owning their family planning programs by strengthening their capacity and self-reliance. TCI has since contributed to 4.65 million additional family planning clients and helped garner $73.1 million in family planning funding allocation from local governments. The authors aim to help other public health organizations effectively apply leadership and management concepts to their scale-up design and implementation. In this review, we summarize the eight key lessons on leadership and management from TCI: (I) The platform model is a transformative and effective organizational structure for a large-scale family planning program. (II) Shared vision and transformational leadership are crucial to the success of any organization, especially those with a platform model. (III) A systems thinking approach is needed to address wicked public health problems like family planning. (IV) A learning organization cultivates a culture of innovation and continuous improvement. (V) Near-real-time data spurs the organization’s evidence-based management. (VI) Strategy designs should be developed and implemented at different levels of the platform. (VII) Local program designs should be informed by landscaping and root cause analysis. (VIII) A digital platform is key to facilitating large-scale online learning, technical and managerial coaching, and a community of practice. Despite its success, TCI is navigating challenges around access to leadership development programs for all its staff, post-graduation difficulties in some cities, and getting buy-in from more traditional donors given its unique platform model. While TCI’s current efforts are focused on family planning, its model is adaptable to other health areas related to primary health care and maternal, newborn, and child health.