Objective To explore the application value of echocardiography in the differential diagnosis of Fabry disease and hypertrophic cardiomyopathy (HCM). Methods Baseline data and echocardiographic parameters of Fabry disease patients and HCM patients admitted to the First Affiliated Hospital of Xi’an Jiaotong University between January 2022 and January 2024 were selected and compared between groups. The diagnostic ability for Fabry disease and HCM was analyzed using receiver operating characteristic curves and area under the curve (AUC). Results A total of 16 Fabry disease patients and 41 HCM patients were included. The Fabry disease group had lower age, body mass index, proportion of electrocardiogram abnormalities, and smoking history than the HCM group (P<0.05); the Fabry disease group had a longer medical history than the HCM group (P<0.05). The maximum thickness of the left ventricular myocardium and the ascending aortic diameter in the Fabry group were both smaller than those in the HCM group (P<0.05). The e-peak velocity in the Fabry group was greater than that in the HCM group (P<0.05). For the differential diagnosis of Fabry disease and HCM, the AUC for the e-peak velocity was 0.698 [95% confidence interval (0.502, 0.894), P<0.05], sensitivity was 41.7%, specificity was 100%, and Youden index was 41.7%. When the three factors were combined, both sensitivity and accuracy were significantly higher than the e-peak. The AUC was 0.773 [95% confidence interval (0.585, 0.961), P<0.05], with a sensitivity of 100% and specificity of 45.5%. There were no statistically significant differences in the 2D-speckle tracking imaging echocardiography parameters between the two groups, including global longitudinal strain of the left ventricle, strain of the apical segment, strain of the basal segment, and so on (P>0.05). Conclusion Echocardiography may have certain significance in the diagnosis of Fabry disease and HCM.