Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to inform weight loss strategies for patients with inborn errors of metabolism. Obese MSUD patients often resist weight loss due to the fear of metabolic decompensation, and their dietary options are limited by dependence on medical foods with fixed nutritional composition. We examined the anthropometric and biochemical effects of metformin in nine adults with severe (classic) MSUD who were instructed to reduce their calorie intake from medical food by 10%. Eight participants (67% female) completed the 52-week study; one withdrew following elective liver transplantation. Baseline median age, body mass index (BMI), and glycosylated hemoglobin (HgbA1C) were 33.8 years (IQR 25.3–41.6), 38.3 kg/m² (IQR 31.6–42.2), and 5.3% (IQR 5.0–5.6), respectively. We titrated the daily metformin dose to a median of 2000 mg (IQR 1000–2000) by week 25, at which time seven (88%) participants successfully reduced total calories from medical food by 10%. Metformin was generally well tolerated. Diarrhea was the most common treatment-related complication, affecting 56% of participants, and limited dose escalation in two (22%) of them. No participant achieved the primary outcome of a > 10% BMI change. However, metformin therapy allowed for modest and significant reductions in weight (−2.8%, p = 0.023), BMI (−2.8 kg/m2, p = 0.016), and calories from medical food without altering plasma leucine concentrations or the proportion of dietary protein from intact sources. Serum triglycerides, high-density lipoprotein, and HgbA1C did not change over the study period. Based on these clinical observations, we conclude that classic MSUD patients can safely use metformin to aid weight loss without triggering metabolic instability, and may therefore tolerate more aggressive weight loss strategies.