Grb10 is an adaptor-type signalling protein most highly expressed in tissues involved in insulin action and glucose metabolism, such as muscle, pancreas and adipose. Germline deletion of Grb10 in mice creates a phenotype with larger muscles and improved glucose homeostasis. However, it has not been determined whether Grb10 ablation specifically in muscle is sufficient to induce hypermuscularity, or impact whole body glucose metabolism. In this study, we generated muscle-specific Grb10-deficient mice (Grb10-mKO) by crossing Grb10flox/flox mice with mice expressing Cre recombinase under control of the human skeletal actin (HSA) promoter. One year old Grb10-mKO mice had enlarged muscles, with increased cross-sectional area of fibers compared to WT. This degree of hypermuscularity did not impact on whole body glucose homeostasis under basal conditions. However, hyperinsulinemic/euglycemic clamp studies revealed that Grb10-mKO mice had increased glucose uptake into muscles compared to WT mice. Insulin signalling was enhanced at the level of phospho-Akt in muscle of Grb10-mKO mice compared to WT, consistent with a role of Grb10 as a modulator of proximal insulin receptor signalling. We conclude that ablation of Grb10 in muscle is sufficient to impact on muscle size and metabolism, supporting an important role for this protein in growth and metabolic pathways.