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Impaired post-prandial skeletal muscle glucose uptake plays a pivotal role in the development of type 2 diabetes mellitus (T2DM), yet pharmacological strategies to enhance muscle glucose uptake are limited. Previous (pre)clinical research revealed that β₂-adrenergic receptor (β2-AR) stimulation enhances glucose uptake, but its clinical relevance in individuals susceptible to developing T2DM is unknown. Here we determined in a double-blinded, placebo-controlled, crossover study (ClinicalTrials.gov-identifier: NCT04921306), the effects of a 4-week treatment with the β₂-adrenergic agonist clenbuterol (40 μg/day) on insulin-stimulated glucose uptake in the quadriceps muscle (primary outcome) and brown adipose tissue (BAT) (secondary outcome) using ¹⁸F-FDG PET-MRI during a hyperinsulinemic-euglycemic clamp in individuals with overweight or obesity (age: 40-70 years, BMI: 25-35 kg/m²). A total of 14 participants were recruited and randomized. Insulin-stimulated glucose uptake tended to improve in vastus lateralis (15%, p = 0.072) and increased significantly in the hamstring (13%, p = 0.039) muscle, while BAT uptake (p = 0.720) remained unaffected. These findings suggest potential therapeutic benefits of β₂-AR stimulation for improving muscle-specific glucose uptake in individuals with or at risk for developing diabetes.