Exposure to toxic metals impacts obesity and type 2 diabetes (T2DM) risk. Yet, the underlying mechanisms remain largely unknown. Gut microbiota has been strongly associated with progression of cardiometabolic risk. To determine whether high metal exposures and gut dysbiosis interact to promote metabolic dysregulation and cardiometabolic risk, we assessed relationships between these factors. We analyzed cross-sectional associations between arsenic, lead, mercury, cadmium, and cardiometabolic health markers in 178 randomly selected African-origin adults (52% female, 51% obese, mean age=43.0±6.4 years) from Ghana, South Africa, Seychelles, Jamaica, and USA. Metal levels were dichotomized to high or low at the median level of each metal. We analyzed associations between gut microbiome taxa, metal levels, clinical measures (BMI, fasting blood glucose, and blood pressure) and diagnoses (hypertension, obesity, and diabetes status). High vs. low lead and arsenic exposures had a significant effect on beta diversity (p <0.05). 71 taxa were associated with high lead levels: 30 with elevated BMI, 22 with T2DM, and 23 with elevated fasting blood glucose (p<0.05). 115 taxa were associated with high arsenic levels: 32 with elevated BMI, 33 with T2DM, and 26 with elevated blood glucose (p<0.05). Of the taxa associated with high lead and arsenic exposure and either elevated BMI or fasting blood glucose, porphyrin metabolism was the most enriched metabolic pathway. These data collectively provide the first findings in a human study that the gut microbiome may drive the association between lead and arsenic exposure and obesity and T2DM risk.