Built environment attributes may be related to cardio-metabolic diseases (e.g. type 2 diabetes, heart disease and stroke) and their risk factors, potentially by influencing residents' physical activity. However, existing literature reviews on the built environment and health for the most part focus on obesity as the outcome and rely on cross-sectional studies. This systematic review synthesized current evidence on longitudinal relationships between built environment attributes and cardio-metabolic health outcomes among adults and on the potential mediating role of physical inactivity. By searching eight databases for peer-reviewed journal articles published in the English language between January 2000 and July 2016, the review identified 36 articles. A meta-analysis method, weighted Z-test, was used to quantify the strength of evidence by incorporating the methodological quality of the studies. We found strong evidence for longitudinal relationships of walkability with obesity, type 2 diabetes and hypertension outcomes in the expected direction. There was strong evidence for the impact of urban sprawl on obesity outcomes. The evidence on potential mediation by physical activity was inconclusive. Further longitudinal studies are warranted to examine which specific built environment attributes influence residents' cardio-metabolic health outcomes and how physical inactivity may be involved in these relationships.