Malaria, diarrhea and acute respiratory infections (ARIs) are the major causes of mortality in young children in sub-Saharan Africa. Here we provide support for the hypothesis that children can be protected from these diseases by improvements in house design. We designed a novel double-story house, called a Star Home, to provide an insect-proof, cleaner, cooler and smoke-free environment, with a reliable supply of water and sanitation. We conducted a cluster-randomized controlled trial where households with children under 13 years of age were randomly allocated (1:4.7) to living in 110 Star Homes or in 513 traditional mud and thatched-roofed houses. The primary outcome of childhood malaria incidence was met: after 3 years, children living in Star Homes had 44% less malaria (incidence rate ratio (IRR): 0.56 (95% confidence interval (CI): 0.43-0.72), P < 0.0001) compared to children living in traditional homes. Children in Star Homes had 30% less diarrhea (IRR: 0.70 (95% CI: 0.53-0.91), P = 0.0070) and 18% less ARIs (IRR: 0.82 (95% CI: 0.73-0.93), P = 0.0010) than children living in traditional homes. Children under 5 years of age living in Star Homes were also taller for their age than those living in traditional homes. Our house design is intended to inspire those working in the building sector and with local communities to develop innovative designs for healthier homes. Major improvements in rural house design have the potential to make a substantial public health impact across hot, humid regions of Africa. ClinicalTrials.gov: NCT04529434 .