Objective The aim of this study was to explore the effect and possible mechanism of aerobic exercise and EMPA on ISO induced pathological cardiac remodeling. Methods The mice were randomly divided into Con group, ISO group, EX+ISO group, EMPA+ISO group and EX+EMPA+ISO group. The exercise group mice were continuously trained for 6 weeks, the EMPA group mice were continuously gavaged for 4 weeks, and all ISO group mice were subcutaneously injected with ISO for 7 days before dissection. The whole heart mass index, left heart mass index, heart mass to tibial length ratio, and left heart mass to tibial length ratio of mice were calculated through weighing and measurement. HE staining, Sirius red staining and WGA staining were used to observe the pathological changes, collagen fiber deposition and myocardial cell cross-sectional area in mice hearts. The qRT-PCR, Western blot and immunofluorescence staining were used to detect the expression of genes and proteins related to cardiac fibrosis and hypertrophy, macrophage infiltration, as well as the expression of genes and proteins related to ferroptosis and PI3K/AKT pathway in mice. Results (1) Compared with ISO group, EX+ISO group had a downward trend in whole heart mass index, left heart mass index, heart mass to tibial length ratio and left heart mass to tibial length ratio. EMPA+ISO group had a significant decrease in whole heart mass index and left heart mass index, heart mass to tibial length ratio and left heart mass to tibial length ratio were both down regulated. EX+EMPA+ISO group had a significant decrease in whole heart mass index, the other three indicators were all down regulated. (2) Compared with ISO group, the myocardial cells in three intervention groups were arranged more orderly, with a significant reduction in inflammatory cell infiltration, as well as a significant reduction in the area of cardiac fibrosis and the cross-sectional area of myocardial cells. (3) Compared with ISO group, the mRNA and protein expressions of Col 1 and Anp were significantly reduced in three intervention groups. The mRNA expression of Col 3 in EMPA+ISO group and EX+EMPA+ISO group was significantly reduced, and the mRNA expression of Col 3 in EX+ISO group showed a downward trend. (4) Compared with ISO group, the number of macrophages infiltration and the mRNA level of Il-6 were significantly reduced in three intervention groups. (5) Compared with ISO group, the mRNA levels of Nrf2 and Gpx4 were upregulated in three intervention groups, with a significant increase in GPX4 protein expression and a significant decrease in HO-1 protein expression. (6) Compared with ISO group, the mRNA level of Pi3k in EX+ISO group was significantly increased, the mRNA level of Pi3k in EMPA+ISO group and EX+EMPA+ISO group was upregulated. The mRNA level of Akt in three intervention groups showed an upward trend. The protein expressions of PI3K and p-AKT in EX+ISO group were significantly increased, and the protein expressions of PI3K and p-AKT in EMPA+ISO group and EX+EMPA+ISO group showed an increasing trend. Conclusions The moderate intensity aerobic exercise, the novel hypoglycemic drug EMPA, and their combination can alleviate ISO induced pathological cardiac remodeling, the mechanism may be related to the activation of the PI3K/AKT signaling pathway and inhibition of cardiac ferroptosis.