In 2021, the Adolescents 360 (A360) project pursued a human-centered design (HCD) process to layer complementary economic empowerment components on top of its existing sexual and reproductive health (SRH) interventions targeting adolescent girls aged 15 to 19. Given the volume of evidence informing successful approaches for improving economic and empowerment outcomes for adolescents, we pursued an intentionally evidence-informed and gender-intentional design process, while trying to also respond directly to user insights. In this open letter, we share how we utilized and validated the evidence-base while applying the core tenets of HCD (empathy and user insights) to design holistic, layered programming for girls. We describe three overarching categories which depict how we used the existing evidence and new user insights to strengthen our design process. Often the evidence base allowed us to expedite finding a solution that worked for our users. However, at times there was a disconnect between what we knew worked in the evidence base and what our users said they wanted. New insights also allowed us to build a greater understanding of our users’ lived experiences where there were existing evidence gaps. We were aided by the engagement of a technical partner, BRAC, who synthesized evidence for our design teams and functioned as an ‘on demand’ support mechanism as questions and challenges arose. Yet, the volume of information to absorb almost guaranteed that we would miss out on the opportunity to apply certain evidence-based practices. We encourage researchers to consider how to make evidence more easily digestible to practitioners and for the whole community of practice to work together to identify what questions need to be asked to effectively operationalize evidence in a local context.