Exercise-induced ionic changes can modulate the interaction between liraglutide and the glucagon-like peptide-1 receptor (GLP-1R). To investigate this, molecular dynamics simulations and in vivo experiments using streptozotocin-induced diabetic rats were performed. Under exercise-mimicking ionic conditions (NaCl 129 mM, KCl 8.5 mM), the simulations revealed enhanced stability of the liraglutide-GLP-1R complex, evidenced by reduced interatomic distances, a lower radius of gyration, increased ligand flexibility (as indicated by RMSF), higher solvent-accessible surface area, and stronger binding energy. Structural analysis using PDBsum identified one salt bridge, two hydrogen bonds, and eighty-nine non-bonded contacts between liraglutide and key receptor residues, confirming a robust and stable interaction. In diabetic rats, the combined treatment with liraglutide and exercise significantly decreased body weight and plasma glucose levels (P < 0.001), improved lipid profiles, and enhanced insulin sensitivity. These effects were accompanied by a significant increase in the expression of mitochondrial regulators PGC-1α and UCP-1 (P < 0.01), indicating enhanced mitochondrial biogenesis and thermogenic capacity.