STEM (science, technology, engineering, and mathematics) plays a key role in accelerating economic growth and developing innovative solutions to pressing challenges facing the African continent. Over the past few decades, much work has been done to develop university systems in African countries in recognition of the role that high-caliber teaching and research in STEM fields play in economic development. African universities and their governments have made many of these gains through partnering across countries and sectors. Often, however, these efforts are based on individual connections and do not lead to long-term change. Inspired by STEM's potential to tackle African and global challenges, a group of academic leaders has come together to explore a synergistic approach to transform African institutions of higher education and increase the global engagement of U.S. institutions. They developed an initial vision for a next-generation Africa-U.S. STEM initiative that would take place for at least 10 years, with funds of at least $10 million annually from governments, the private sector, philanthropies, and other organizations. To obtain input from stakeholders on how such an initiative could develop, the group held a virtual workshop March 14-16, 2022, convened by the National Academies of Sciences, Engineering, and Medicine. This publication summarizes the presentations and discussions of the workshop. [Paula Tarnapol Whitacre served as Rapporteur. Contributors include Science and Engineering Capacity Development Unit and Policy and Global Affairs.]