question: BACKGROUND: Human-centered design (HCD) is increasingly being used as a complementary approach to traditional global health methods due to its ability to bring new ideas to entrenched problems, integrate multiple stakeholder perspectives, and bring in a strong human lens among other advantages. To reap these benefits, public health and design practitioners in global health programs can learn from the early experiences of integrating HCD to advance these efforts. OBJECTIVE: This article distills lessons gathered from 3 programs leveraging HCD to advance global health programming: (1) the “V” program which used an HCD approach to reframe the once-a-day HIV prevention pill from a potentially stigmatizing medicine into empowering self-care; (2) the Adolescents 360 program which integrated HCD to create a service for adolescent girls to access contraception in Ethiopia and to scale this offering nationwide; and (3) Reimagining TA which used HCD to help shift perceptions around traditional technical assistance models to one of co-creation, defining a new approach for non-financial support for health systems strengthening. FINDINGS: To inform global health programs that are considering employing an HCD approach, lessons learned are distilled into 3 categories: (1) planning: considerations for problem definition and project scoping to allow for flexibility and selection of appropriate methods; (2) engaging: reflections on the means to productively engage different stakeholder groups to build alignment, understanding, and buy-in; (3) applying: adoption of new ways of working during implementation to best take advantage of the benefits of HCD while promoting long-term program sustainability and learning. CONCLUSION: These lessons represent an important step on the pathway to demonstrate the contributions of HCD to improving the effectiveness of health programs at a time when the global health community needs the most robust set of tools possible to meet the demands of our current pandemic context and beyond.