We explored the outcomes and challenges encountered during a 12-year collaborative development endeavor in Tanzania, focused on enhancing the healthcare system. The Health Promotion and System Strengthening (HPSS) project, supported by the Swiss Government and implemented by the Swiss Tropical and Public Health Institute (Swiss TPH) from 2011 to 2023, aimed to strengthen various aspects of Tanzania’s healthcare landscape. This included reforms in health insurance through the improved Community Health Fund (iCHF), the establishment of a public–private partnership to optimize the health commodity supply chain via a Prime Vendor System (Jazia PVS), the implementation of health technology management innovations, and the facilitation of participatory community and school health promotion initiatives. Operating in a multisectoral, interdisciplinary, and systemic manner, the HPSS project employed a variety of interconnected strategies, focusing on key entry points within the Tanzanian health system, starting from district level to national policies. These efforts followed a three-stages approach to reach a sustainable adoption of the innovations, going through the process of service and product innovation, integration into service delivery systems, and finally their adoption in the respective institutional policies. Each stage presented distinct frameworks and challenges, detailed in this article. The development of innovative concepts was complemented by capacity building through on-the-job training, establishment of new accredited training programs for pre-service trainings, and the development of new IT systems integrated into the governmental IT environment, as well as efforts to improve transparency, accountability, and governance. Activities in these fields were guided by operational research, following the translational approach of Swiss TPH to go from innovation and validation to application. The example of the HPSS project highlights the cycle of developing and testing innovations at the community and district level, followed by endeavoring national-level integration and policy adjustments, consequently resulting in improved service delivery at the district and community level.