Adolescent sexual and reproductive health gained particular traction in Mozambique following the 1994 International Conference on Population and Development leading to the inception of Programa Geração Biz, a multi-sectoral initiative that was piloted starting in 1999 and fully scaled-up to all provinces by 2007. We conducted a systematic review of the literature to gather information on Programa Geração Biz and analyzed how it planned and managed the scale-up effort using the WHO-ExpandNet framework. Programa Geração Biz’s activities comprised a clear and credible innovation. Appropriate resource and user organizations further facilitated national scale-up. Challenges relating to the complex nature of the multi-sectoral approach and resistance due to norms about adolescent sexual and reproductive health hindered scaling-up in some geographic areas. The national government exhibited commitment and ownership to Programa Geração Biz through budgetary support and integration into multiple policies. This study adds to the documentation of successful scaling-up strategies that can provide guidance for policy makers and program managers.