BACKGROUND: Land-use changes in city fringes due to urbanization can lead to a reduction of greenspace that may reduce its associated health benefits. OBJECTIVES: We evaluated the association between changes in residential surrounding built-up land use and cardiometabolic risk factors in an urbanizing peri-urban area of south India and explored the mediating roles of air pollution, physical activity, and stress in these associations. METHODS: We analyzed data on 6,039 adults from the third follow-up of the Andhra Pradesh Children and Parent Study (APCAPS) cohort (2010-2012). We generated trajectories of change in residential surrounding built-up land use (buffer areas) from 1995-2009 (stable, slow increase, fast increase) using remote sensing data and image classification methods. We estimated associations between built-up land use trajectories and natural log-transformed blood pressure, waist circumference, triglycerides, fasting glucose, and non-high-density lipoprotein (non-HDL) cholesterol using linear mixed models. We accounted for multiple mediators and the multilevel structure of the data in mediation analyses. RESULTS: We observed positive associations between a fast increase in built-up land use within 300m of the home and all cardiometabolic risk factors. Compared with participants with stable trajectories, those with the largest increase in built-up land use had 1.5% (95% CI: 0.1, 2.9) higher systolic blood pressure, 2.4% (95% CI: 0.6, 4.3) higher diastolic blood pressure, 2.1% (95% CI: 0.5, 3.8) higher waist circumference, and 1.6% (95% CI: -0.6, 3.8) higher fasting glucose in fully adjusted models. Associations were positive, but not statistically significant, for triglycerides, fasting glucose, and non-HDL cholesterol. Physical activity and ambient particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) partially mediated the estimated associations. Associations between fast build-up and all cardiometabolic risk factors except non-HDL cholesterol were stronger in women than men. DISCUSSION: Increases in built-up land use surrounding residences were consistently associated with higher levels of cardiometabolic risk factors. Our findings support the need for better integration of health considerations in urban planning in rapidly urbanizing settings. https://doi.org/10.1289/EHP5445.