In 2004, CARE launched an innovative education initiative funded by a private donor (Patsy Collins) to improve learning and future life options for marginalized adolescent girls. Informed by over a decade of lessons learned and endline evaluation data from previous cohorts about effective and gender transformative programming at the primary education level, the Patsy Collins Trust Fund Initiative’s (PCTFI’s) third cohort (2015-2020) focuses on strengthening education quality, improving learning outcomes, furthering gender equity, and promoting empowerment of adolescents of lower secondary age in Cambodia, Nepal, Rwanda, Mali, Zimbabwe, and Kenya. Key design elements are integrated models to foster foundational skills development, increased sexual and reproductive health information and capabilities, and economic empowerment as well as strategic partnerships to promote social accountability, improved education service delivery, and greater adolescent awareness of and access to markets. PCTFI Cohort 3 uses diverse, context-specific approaches responsive to the needs of in- and out-of-school adolescents to enhance teaching and learning. For teachers, professional development includes gender-sensitive classroom management practices, student-centered pedagogies, and meaningful ICT integration to promote critical thinking and conceptual understanding. For older children and out-of-school adolescents, alternative and accelerated learning options help develop transferable life and vocational skills and foundational literacy and numeracy to transition into secondary school or the world of work. This paper will explore lessons emerging to date on the use of multi-sectoral approaches and key partnerships with communities, schools, traditional and non-traditional education stakeholders, financial institutions, and the ICT sector to promote sustainable development goals (SDGs 3, 4, and 5). The paper will examine how these approaches and partnerships are contributing to improvements in adolescent girls’ access, retention, learning and perceptions of girls’ leadership as well as combating harmful social and gender norms. The paper will also highlight key innovations from each country that can be adapted and scaled to multiply their impact.