The aim of this study was to examine the efficacy of intensive medical nutrition therapy (MNT) plus metformin in preventing gestational diabetes mellitus (GDM) among high-risk Mexican women. An open-label randomized clinical trial was conducted. Inclusion criteria were pregnant women with three or more GDM risk factors: Latino ethnic group, maternal age >35 years, body mass index >25 kg/m2, insulin resistance, and a history of previous GDM, prediabetes, a macrosomic neonate, polycystic ovarian syndrome, or a first-degree relative with type 2 diabetes. Women before 15 weeks of gestation were assigned to group 1 (n = 45): intensive MNT-plus metformin (850 mg twice/day) or group 2 (n = 45): intensive MNT without metformin. Intensive MNT included individual dietary counseling, with ≤50% of total energy from high carbohydrates. The primary outcome was the GDM incidence according to the International Association of Diabetes Pregnancy Study Groups criteria. There were no significant differences in baseline characteristics and adverse perinatal outcomes between the groups. The GDM incidence was n = 11 (24.4%) in the MNT plus metformin group versus n = 7 (15.5%) in the MNT without metformin group: p = 0.42 (RR: 1.57 [95% CI: 0.67–3.68]). There is no benefit in adding metformin to intensive MNT to prevent GDM among high-risk Mexican women. Clinical trials registration: NCT01675310.