Adaptation is essential for mitigating adverse human health effects from increasing heat exposure. However, we currently lack evidence – generated through empirical studies – guiding the uptake of interventions to reduce heat stress in low- and middle-income countries (LMICs). Preliminary findings from our ongoing trial in Nouna, Burkina Faso, show that affordable sunlight reflecting cool-roof coatings reduces indoor temperature up to 2.7 °C leading to possible health benefits. We leverage our expertise in executing housing-health intervention trials to conduct a global multi-centre study of cool-roof effectiveness on health (environmental and economic) outcomes in four urban LMICs – Ouagadougou, Burkina Faso (sub-Saharan Africa), Ahmedabad, India (Asia), Niue (Oceania), and Sonora, Mexico (Latin America). Selected sites represent hotspots where people experience a triple burden from heat exposure, chronic health issues and vulnerable housing conditions (slums, informal settlements and low socioeconomic housing). The four sites exhibit diversity in climate profiles, level of socioeconomic development, population density and rates of urbanisation. Our trial will test the reproducibility of results globally and quantify whether cool roofs are an effective passive home cooling intervention with beneficial health effects for vulnerable populations. Findings will inform global policy responses on adaptation to increasing heat exposure from climate change.