Many effective health system innovations fail to reach those who need them most, falling short of the goal of universal health coverage. In the 5 years since the Federal Ministry of Health in Ethiopia localised the Practical Approach to Care Kit (PACK) programme to support primary care reforms, PACK has been scaled-up to over 90% of the country’s primary care health centres. Known as the Ethiopian Primary Healthcare Clinical Guideline (EPHCG), the programme comprises a comprehensive, policy-aligned clinical decision support tool (EPHCG guide) and an implementation strategy to embed comprehensive, integrated care into every primary care consultation for individuals over 5 years of age, while addressing barriers to streamlined primary healthcare delivery. We describe the components of the EPHCG programme and the work done to establish it in Ethiopia. Yamey’s framework for successful scale-up is used to examine the programme and health system factors that enabled its scale-up within a 5-year period. These included high-level ministry leadership and support, a cascade model of implementation embedded in all levels of the health system, regular EPHCG guide and training material updates and strategies to generate stakeholder buy-in from managers, health workers, patients and communities. Challenges, including stakeholder resistance, training fidelity and quality and procurement of medicines and diagnostic tests, are described, along with efforts to resolve them. Insights and learnings will be of interest to those implementing PACK programmes elsewhere, and managers and researchers responsible for design and delivery of health systems strengthening innovations at scale in low-income and middle-income countries.