Objective To explore the effect and possible mechanism of aerobic exercise and empagliflozin (EMPA) on isoproterenol (ISO)-induced pathological cardiac remodeling. Methods Mice were divided randomly into control (Con), ISO, exercise (EX) + ISO, EMPA + ISO, and EX + EMPA + ISO groups. Mice in the EX groups were trained continuously for 6 weeks, mice in the EMPA groups were gavaged continuously for 4 weeks, and mice in the ISO groups were injected subcutaneously with ISO for 7 days before dissection. After euthanasia, the whole heart mass index, left heart mass index, heart mass to tibial length ratio, and left heart mass to tibial length ratio were calculated by weighing and measuring. Pathological changes, collagen fiber deposition, and myocardial cell cross-sectional area in the hearts were detected by hematoxylin and eosin, Sirius red, and wheat germ agglutinin staining. The expression levels of genes and proteins related to cardiac fibrosis and hypertrophy, macrophage infiltration, ferroptosis, and the phosphoinositide 3-kinase (PI3K)/AKT pathway were examined by quantitative reverse transcription-polymerase chain reaction, Western Blot, and immunofluorescence staining. Results (1) The whole heart mass index, left heart mass index, heart mass to tibial length ratio, and left heart mass to tibial length ratio showed downward trends in the EX + ISO group compared with the ISO group. The whole heart mass index and left heart mass index were significantly decreased in the EMPA + ISO group (P<0.01, P<0.05), and the heart mass to tibial length ratio and left heart mass to tibial length ratio were both down regulated. Mice in the EX + EMPA + ISO group had a significant decrease in whole heart mass index (P<0.05), and the other three indicators were all down-regulated. (2) Myocardial cells were more orderly in the three intervention groups compared with the ISO group, with significant reductions in inflammatory cell infiltration (P<0.01), the area of cardiac fibrosis, and the cross-sectional area of myocardial cells (P<0.001). (3) The mRNA and protein expression levels of Col 1 and Anp were significantly reduced in the three intervention groups compared with the ISO group (P<0.05, P<0.01, P<0.001). Col 3 mRNA expression significantly reduced in the EMPA + ISO and EX + EMPA + ISO groups (P<0.05), and showed a downward trend in the EX + ISO group. (4) Macrophage infiltration and IL-6 mRNA levels were significantly reduced in the three intervention groups compared with the ISO group (P<0.05, P<0.01, P<0.001).(5) Nrf2 and Gpx4 mRNA levels were upregulated in the three intervention groups compared with the ISO group, with a significant increase in GPX4 protein expression (P<0.01, P<0.001) and a significant decrease in HO-1 protein expression (P<0.01, P<0.001). (6) Pi3k mRNA levels were significantly increased in the EX + ISO group compared with the ISO group (P<0.05), and Pi3k mRNA was upregulated in the EMPA + ISO and EX + EMPA + ISO groups. Akt mRNA levels showed an upward trend in the three intervention groups. PI3K and phospho-AKT protein levels were significantly increased in the EX + ISO group (P<0.01, P<0.05), and showed an increasing trend in the EMPA + ISO and EX + EMPA + ISO groups. Conclusions Moderate intensity aerobic exercise, the novel hypoglycemic drug EMPA, and their combination can alleviate ISO-induced pathological cardiac remodeling, possibly via a mechanism related to activation of the PI3K/AKT signaling pathway and inhibition of cardiac ferroptosis.