Health inequities are undermining life-saving HIV care, prevention, and harm reduction services for people with and affected by HIV. HIV activism has been a driver for change in improving the HIV response, from securing access to life-saving HIV treatment and challenging socio-cultural structures to demanding greater and meaningful involvement of communities. However, many initiatives and actions to progress the HIV response face a myriad of structural challenges and resistance. Harnessing the against-the-grain persistence of HIV activism, our conceptual article proposes a direction for HIV activism in Asia using a structured review of scholarly literature and policy documents to identify the successes and gaps in the HIV response, extrapolating the cost of inaction and indifference to the future of the HIV response, and providing recommendations for future health research, policy, and practice and forming meaningful alliances. We introduced a Four-fold HIV Activism Agenda and HIV Activism Framework for Asia to improve the HIV response across Asian countries. We emphasise the urgency to address the immediately actionable drivers of health inequities in the HIV response in the region, especially in centring communities most affected by HIV, and improving individual well-being. It necessitates addressing health inequities more systematically and collaboratively with a scaled approach.