Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium glucose cotransporter-2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low dose streptozotocin; STZ). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyper-activation of JNK/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was 2-fold higher in STZ compared to Control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak and impaired metabolic health (siOGTT). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by co-therapy with SGLT2i.