There is a surge in chronic diseases in the developing world, driven by a high prevalence of cardio-metabolic risk factors. This study described differences in prevalence of obesity and cardio-metabolic risk factors between urban and rural settlements in the Ashanti Region of Ghana. This comparative cross-sectional study included 672 participants (median age 50 years), of which 312 were from Kumasi (urban) and 360 from Jachie-Pramso (rural). Demographic, anthropometric and other cardio-metabolic risk factors were gathered and venous blood samples were drawn for biochemical assays. Results suggested significant differences in diastolic blood pressure (80.0 mmHg vs 79.5 mmHg; p = 0.0078), and fasting blood sugar (5.0 mmo/l vs 4.5 mmol/l; p < 0.0001) between the two groups. Further differences in anthropometric measures suggested greater adiposity amongst participants in the urban area. Participants in the urban area were more likely than rural participants, to have high total cholesterol and LDL-c (p < 0.0001 respectively). Risk factors including BMI ≥ 25 (p < 0.0001), BMI ≥ 30 (p < 0.0001), high waist circumference (p < 0.0001), high waist-to-height ratio (p < 0.0001) and alcohol consumption (p = 0.0186) were more prevalent amongst participants in the urban area. Markers of adiposity were higher amongst females than males in both areas (p < 0.05). In the urban area, hypertension, diabetes and lifestyle risk factors were more prevalent amongst males than females. Differences in risk factors by urban/rural residence remained significant after adjusting for gender and age. Obesity and cardio-metabolic risk factors are more prevalent amongst urban settlers, highlighting an urgent need to avert the rise of diet and lifestyle-related chronic diseases.