Achieving global targets to end the HIV/AIDS epidemic as a public health threat by 2030 and beyond requires enhanced health system capacity for HIV prevention at national and subnational levels. Specifically, this system's capacity must enable countries to reach high-risk populations effectively, systematically engage communities to generate demand for HIV prevention services, build diverse delivery channels to meet this demand and address structural barriers that undermine prevention programmes. Integrating these capacities at the local level is especially critical to creating sustainable uptake and impact of emerging highly efficacious prevention options, such as long-acting injectable pre-exposure prophylaxis. Decentralised, locally led approaches that reflect the local context-yet are linked to national systems and policies-are needed to embed these capacities and strengthen the ability of local governments to coordinate and implement HIV prevention. Within this framework, the Government of Malawi is developing a district-based approach to enhance local institutional capacity for more effective and sustainable HIV prevention, starting in Blantyre-a large urban district noted for its high HIV incidence. This article provides the conceptual basis for, and early implementation experience of, the Blantyre Prevention Strategy (BPS), a health systems-based approach to HIV prevention that directs investments towards embedding essential functions within Blantyre City and District. The approach includes developing district-led systems and capabilities in effective disease surveillance and data-driven targeting, demand generation, quality service delivery and promoting the sustained use of HIV prevention interventions. Early learnings from BPS offer lessons for other low- and middle-income countries seeking to implement HIV prevention strategies that bolster their health system capacity and integrate with broader health responses.