BACKGROUND: Rapid population growth in Africa requires an urgent expansion and improvement of housing options. Improving housing presents a promising opportunity for malaria control by reducing indoor exposure to mosquitoes. We measured recent changes in house design in rural Uganda and evaluated their association with malaria in relation to a mass scale-up of control efforts. METHODS: This analysis was part of a cohort study designed to compare temporal changes in malaria incidence from a cohort of children and adults with temporal changes in malaria test positivity rate from health facility surveillance. All children aged 6 months to 10 years (n=384) living in 107 households in Nagongera sub-country, Tororo, Uganda, were given long-lasting insecticide-treated nets and followed between Aug 19, 2011, and June 30, 2017. Repeat rounds of indoor residual spraying of insecticide were initiated on Dec 5, 2014. Socioeconomic data were collected at two timepoints (Sept 25-Oct 9, 2013 and June 21-July 11, 2016) and houses were classified as modern (cement, wood, or metal walls, tiled or metal roof, and closed eaves) or traditional (all other homes). Associations between house design and three outcomes were evaluated before and after the introduction of indoor residual spraying: human biting rate estimated monthly in each household using US Centers for Disease Control and Prevention light traps; parasite prevalence measured routinely by microscopy every 3 months before indoor residual spraying and monthly after indoor residual spraying; and malaria incidence measured by passive surveillance. FINDINGS: The implementation of indoor residual spraying was associated with significant declines in human biting rate (33·5 vs 2·7 Anopheles per house per night after indoor residual spraying, p<0·0001), parasite prevalence (32·0% vs 14·0%, p<0·0001), and malaria incidence (3·0 vs 0·5 episodes per person-year at risk, p<0·0001). The prevalence of modern housing increased from 23·4% in 2013 to 45·4% in 2016 (p=0·001). Compared with traditional houses, modern houses were associated with a 48% reduction in human biting rate before indoor residual spraying (adjusted incidence rate ratio [aIRR] 0·52, 95% CI 0·36-0·73, p=0·0002), and a 73% reduction after indoor residual spraying (aIRR 0·27, 0·17-0·42, p<0·0001). Before indoor residual spraying, there was no association between house type and parasite prevalence, but after indoor residual spraying there was a 57% reduction in the odds of parasitaemia in modern houses compared with traditional houses, controlling for age, sex, and socioeconomic position (adjusted odds ratio 0·43, 95% CI 0·24-0·77, p=0·004). House type was not associated with malaria incidence before or after indoor residual spraying. INTERPRETATION: House design improved rapidly in rural Uganda and was associated with additional reductions in mosquito density and parasite prevalence following the introduction of indoor residual spraying. Changes to house design in endemic Africa, including closing eaves and the replacement of traditional building materials, might help further the gains achieved with more widely accepted malaria control interventions. FUNDING: US National Institutes of Health, Bill & Melinda Gates Foundation, and Medical Research Council UK.