Chronic endemic regional hydroarsenicism (CERHA) is a global issue that affects over 200 million people exposed to arsenic (As) in drinking water. This includes 1.75 million individuals residing in La Comarca Lagunera, a region in north-central Mexico. Arsenic levels in this region typically exceeds the WHO guideline of 10 µg L−1. Biochemical alterations related to the human As metabolism may increase the risk of overweight and obesity (O&O), type 2 diabetes (T2D), and hypertension (AHT). In our study, we investigated the role of As in drinking water as a risk factor for these metabolic diseases. We focused on populations with historically moderate (San Pedro) and low (Lerdo) drinking water As levels and people with no historical evidence of As water contamination. The exposure assessment to As was based on measurements of the drinking water (medians 67.2, 21.0, 4.3 µg L−1) and urinary As concentrations in women (9.4, 5.3, 0.8 µg L−1) and men (18.1, 4.8, 1.0 µg L−1). A significant correlation between As in drinking water and urine evidenced the As exposure in the population (R2= 0.72). Adjusted odds ratios with 95% confidence intervals evidenced higher chances of being diagnosed with T2D (1.7, 1.2–2.0) and AHT (1.8, 1.7–1.9) in individuals living in San Pedro than those in Lerdo. Still, there was no significant association with obesity. Individuals living in CERHA towns were found to have a higher risk of obesity (1.3–1.9), T2D (1.5 to 3.3), and AHT (1.4 to 2.4) compared to those residing in non-CERHA towns. Finally, obesity is more probable in women [inverse of OR and 95%CI 0.4 (0.2–0.7)] compared to men, while men is more likely to be diagnosed with T2D [OR = 2.0 (1.4–2.3)] and AHT [OR = 2.0 (1.5–2.3)] than women, independently of the municipality.