Background: High-fat diet (HFD) had a complex impact on the myocardium and resulted in diastolic dysfunction and hypertension on left ventricular (LV) hypertrophy, which can cause cardiac remodeling. Two-dimensional speckle tracking echocardiography (2D-STE) provided deformation information of the LV, which had been reported to be valuable in identifying preclinical or subtle myocardial dysfunction. This study assessed whether 2D-STE can investigate the effect of HFD on cardiac function in mice. Methods: Animals were grouped into HFD group and normal diet group according to whether they were feeding with HFD. We acquired the echocardiographic image and the mice weight before feeding, at 12th week and 20th week during feeding periods, compared the strain values and traditional echocardiographic measurements in both groups. Results: There was a stepwise increase in body weight both HFD group and normal group over time. There was a distinct statistics difference in body weight at the end of 12th and 20th week between the two groups (all P < 0.05). There was no significant change in traditional echocardiographic measurements of left ventricle in the feeding periods. There was no obvious statistical difference in the strain values of the HFD mice compared to normal mice at 12th week (P > 0.05); however, a significant decrease was observed in longitudinal strain (LS) and circumferential strain (CS) levels (P < 0.05) at 20th week between the two groups. Conclusions: Compared to the normal group, LS and CS values in the HFD mice were evidently decreased despite normal ejection fractions in both groups. 2D STE is sensitive to detect the LV altered cardiac mechanics associated with HFD and can provide valuable information for clinical intervention.