Pathological cardiac hypertrophy (PaCH) leads to heart failure, whereas exercise-induced physiological cardiac hypertrophy (PhCH) represents a benign adaptive response, and counteracts PaCH. Here, we investigated the association of miR-17-5p and IGFBP5 expressions with PhCH through a PhCH group (five mice with 21-days swimming exercise) and healthy controls (n = 5). The PhCH group showed higher body weight (BW), heart weight (HW), HW/BW ratio, ventricular septal thickness, left-ventricular end-diastolic diameter, and left-ventricular end-systolic diameter than control group (p < 0.05 for all). The IGFBP5 expression was significantly reduced, whereas miR-17-5p expression was significantly elevated in PhCH group (p < 0.05). Dual-luciferase assays validated the direct binding of miR-17-5p with IGFBP5. Wheat germ agglutinin staining revealed enlarged cardiomyocytes of PhCH group, while Masson staining disclosed no increase of fibrosis. The reduction of IGFBP5 and elevation of miR-17-5p are associated with PhCH, suggesting their potentials for further researches in myocardial hypertrophy.