IntroductionAdolescent girls and young women (AGYW) in Nepal have disproportionately poor reproductive and maternal health outcomes. In response, Save the Children, the Nepal government, and local partners designed and implemented Healthy Transitions for Nepali Youth, a multi-level integrated intervention. The intervention aimed to improve reproductive, maternal, and newborn health knowledge, attitudes, and behaviors among AGYW, and address gender attitudes and norms in four districts of Karnali Province, Nepal.MethodsMarried and unmarried AGYW aged 15–24 were engaged in a small group, curriculum-based intervention; husbands and families received home visits, using short videos to catalyze discussion; communities were engaged through dialogue-based activities; and the health system was made more adolescent-responsive through quality assessments, training, and supervision. An external organization conducted a quantitative survey with a sample of 786 AGYW intervention participants at baseline and 565 of the same AGYW at endline. Pooled linear regressions were estimated for each indicator to assess the statistical significance of differences between baseline and endline. Focus group discussions and key informant interviews were conducted with AGYW, husbands, families, community leadership, and program implementers. Data analysis was done through STATA 14thversion and NVivo.ResultsThe percentage of AGYW currently using a modern contraceptive method increased significantly, and more AGYW believed that their family was supportive of delaying marriage and motherhood at the endline. Young women’s knowledge of danger signs during labor increased, and there was a significant improvement in essential newborn care practices immediately after birth. AGYW reported shifts towards more gender equitable attitudes and behaviors, including related to decision-making about reproductive and maternal health.ConclusionPositive shifts in reproductive, maternal, and newborn health and gender knowledge, attitudes, and behavior were observed among AGYW, their male partners, and families. The results can inform the design of future interventions to effectively reach this critical population.Trail registrationNot applicable.