Although significant efforts have been made to combat the spread of vector-borne diseases (VBDs), they still account for more than 17% of all infectious diseases. According to the World Health Organization (WHO), there were 216 million estimated cases in 2016, which is a 9.3% decrease from the estimated cases reported one decade earlier. It is known that the built environment, through features such as openings, can propagate the spread of malaria. There have been some significant efforts directed at addressing this risk. This notwithstanding, there are some knowledge gaps that have resulted in a missed opportunity for synergistically tackling the problem of vectors through leveraging design decisions made by built environment professionals. This work assesses the extent to which design decisions in the built environment can have a positive impact on the efforts directed at mitigating the risk of malaria based on selected cases from East Africa. Secondary data derived from relevant urban health journals as well as repositories curated by leading health agencies such as WHO were synthesized and analyzed using a web of causation approach. The outcome of the analysis is a schema of primary and secondary source (risk) factors. The use of the web of causation approach revealed the existing factor-to-factor interactions that could have a reinforcing effect. This information was used to identify the critical linkages and interdependencies across different factors. The outcome of the analysis was mapped against risk factors that can be linked to decisions made during the six primary phases of the construction life cycle: preliminary phase, conceptual design, detailed design, construction, facilities management, and end of life/disuse. The findings of the research have established that 1) there is, in fact, a built environment–related opportunity that can be leveraged to advance the impact of malaria mitigation effort; 2) cross-disciplinary synergies are critical to managing the interdependencies and complexity of malaria risk factors that have a reinforcing effect; and 3) a knowledge-management framework that serves as a decision support tool would be valuable for sharing data under a push-and-pull mechanism, in which data shared in real time can address the timeliness of mitigating the spread of malaria at the earliest stages for the greatest impact. Based on the findings, a conceptual architecture for a decision support framework has been proposed. This will be developed into a knowledge-management platform in subsequent efforts.