Climate change is an escalating public health threat in East and Southern Africa, intensifying disease outbreaks, malnutrition, extreme weather events, and disruptions to healthcare delivery. These impacts disproportionately affect vulnerable populations and expose persistent weaknesses in health-system preparedness, workforce capacity, availability of climate-health data, and translation of evidence into policy. This 54-month regional climate change and health research hub, led by Amref Health Africa in partnership with KPMG Advisory Services East Africa, the University of Botswana, and Africa International University, aims to strengthen gender-responsive and climate-resilient health systems centred on primary health care across an initial fourteen countries in East and Southern Africa. The hub will generate disaggregated and intersectional climate-health evidence, strengthen policymakers’ capacity to use evidence, enhance research and health-workforce capabilities, improve health-system surge capacity, and increase the translation of research into policy and practice. Implementation will involve competitive research subgrants, multidisciplinary scientific peer review, capacity building and mentorship, stakeholder co-production, regional networking, and knowledge mobilization. Gender equality and social inclusion will be embedded throughout research design, implementation, data generation, and dissemination. Research findings will be translated through open-access publications, policy briefs, community engagement, webinars, conferences, and policy dialogues. Ultimately, the hub seeks to establish a sustainable regional ecosystem that generates actionable climate-health evidence, strengthens community and primary healthcare preparedness, informs equitable policy and programming, and enhances the resilience of health systems to climate-related risks and shocks across East and Southern Africa.