BACKGROUND: Traditional rural housing in hot, humid regions of sub-Saharan Africa usually consists of single-level, poorly ventilated dwellings. Houses are mostly poorly screened against malaria mosquitoes and limited airflow discourages the use of bednets resulting in high indoor transmission. This study aims to determine whether living in a novel design house with elevated bedrooms and permeable screened walls reduces malaria, respiratory tract infections, and diarrhoea among children in rural Tanzania. METHODS/STUDY DESIGN: This is a household-randomized, controlled study in 60 villages in Mtwara, Tanzania. A total of 550 households are randomly selected, 110 of which are allocated a novel design house and 440 households continue to reside in traditional houses. A dynamic cohort of about 1650 children under 13 years will be enrolled and followed for 3 years, approximately 330 living in novel design houses and 1320 in traditional rural houses. The primary endpoint is the incidence of malaria; secondary endpoints are incidences of acute respiratory tract infections and diarrhoea diseases detected by passive and active surveillance. Exposure to malaria vectors will be assessed using light traps in all study houses. Structural, economic, and social science studies will assess the durability, cost-effectiveness, and acceptability of the new houses compared with traditional housing. Environmental data will be collected indoors and outdoors in study homes to assess the differences between house typologies. DISCUSSION: This is the first randomized controlled trial to assess the protective efficacy of a new house design targeting malaria in sub-Saharan Africa. The findings of this study could influence the future construction of homes in hot and humid zones of Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT04529434 . Registered on August 27, 2020.