Summary box African countries are not on track to achieve global targets for non-communicable disease (NCD) prevention, driven by an insufficient focus on ecological drivers of NCD risk factors, including poor urban development and the unbridled proliferation of the commercial determinants of health. As the risk factors for NCDs are largely shaped outside the healthcare sector, an emphasis on downstream healthcare service provision to the exclusion of upstream population-level prevention limits the goals of universal health coverage (UHC) and its potential for optimal improvements in (achieving) health and well-being outcomes in Africa. The political will for UHC in Africa will miss the opportunity to turn the tide of this emerging NCD epidemic in Africa, if not oriented to a systems for health rather than a solely healthcare-centric approach. A successful approach needs to proactively incorporate wider health determinants (sectors)—housing, planning, waste management, education, governance and finance, among others—in strategies to improve health. This includes aligning governance and accountability mechanisms and strategic objectives of all ‘health determinant’ sectors for health creation and long-term cost savings. Researchers have a vital role to play, collaborating with policy makers to provide evidence to support implementation and to facilitate knowledge sharing between African countries and globally.