Despite advances in human immunodeficiency virus (HIV) prevention, key populations including men who have sex with men (MSM), sex workers, transgender individuals, people who inject drugs, and adolescent girls and young women (AGYW) continue to experience disproportionately high rates of HIV infection and limited access to prevention services. The recent approval of lenacapavir, a twice-yearly long-acting injectable pre-exposure prophylaxis (PrEP), offers a promising opportunity to overcome adherence challenges associated with daily oral PrEP. However, its successful implementation hinges on addressing the structural and social barriers that have historically excluded these populations from benefiting fully from HIV innovations. While lenacapavir's discreet, long-acting profile holds great promise, its rollout may be undermined by persistent issues such as stigma, criminalisation, lack of youth-friendly services, and health system mistrust. Many individuals from key populations still face legal and social conditions that deter them from accessing clinics, even for biannual injections. Without intentional equity-focused strategies, including peer-led service delivery, policy reform, and community-based outreach, these same barriers could restrict uptake and impact. Innovative solutions such as integrating lenacapavir into trusted drop-in centres, mobile clinics, or combined reproductive health services can enhance accessibility and privacy. Ensuring equitable rollout also demands investment in key population-led organisations, disaggregated data monitoring, and rights-based policy frameworks that affirm agency and safety. Lenacapavir could be a game-changer for HIV prevention, but only if systems evolve to meet the needs of those most affected. Equity must be a deliberate foundation, not a secondary consideration. If we prioritise dignity, inclusivity, and structural reform alongside scientific innovation, lenacapavir can do more than prevent infections; it can help transform global HIV prevention into a tool for justice. The era of long-acting PrEP must not replicate old exclusions but rather break new ground in empowering key populations worldwide.