To identify myocardial fibrosis in hypertrophic cardiomyopathy (HCM) subjects using quantitative cardiac diffusion-weighted imaging (DWI) and to compare its performance with native T1 mapping and extracellular volume (ECV). Thirty-eight HCM subjects (mean age, 53 ± 9 years) and 14 normal controls (mean age, 51 ± 8 years) underwent cardiac magnetic resonance imaging (CMRI) on a 3.0T magnetic resonance (MR) machine with DWI, T1 mapping and late gadolinium enhancement (LGE) imaging as the reference standard. The mean apparent diffusion coefficient (ADC), native T1 value and ECV were determined for each subject. Overall, the HCM subjects exhibited an increased native T1 value (1241.04 ± 78.50 ms), ECV (0.31 ± 0.03) and ADC (2.36 ± 0.34 s/mm²) compared with the normal controls (1114.60 ± 37.99 ms, 0.24 ± 0.04, and 1.62 ± 0.38 s/mm², respectively) (p < 0.05). DWI differentiated healthy and fibrotic myocardia with an area under the curve (AUC) of 0.93, while the AUCs of the native T1 values (0.93), (p > 0.05) and ECV (0.94), (p > 0.05) exhibited an equal differentiation ability. Both HCM LGE+ and HCM LGE− subjects had an increased native T1 value, ECV and ADC compared to the normal controls (p < 0.05). HCM LGE+ subjects exhibited an increased ECV (0.31 ± 0.04) and ADC (2.43 ± 0.36 s/mm²) compared to HCM LGE− subjects (p < 0.05). HCM LGE+ and HCM LGE− subjects had similar native T1 values (1250 ± 76.36 ms vs. 1213.98 ± 92.30 ms, respectively) (p > 0.05). ADC values were linearly associated with increased ECV (R² = 0.36) and native T1 values (R² = 0.40) among all subjects. DWI is a feasible alternative to native T1 mapping and ECV for the identification of myocardial fibrosis in patients with HCM. DWI and ECV can quantitatively characterize the extent of fibrosis in HCM LGE+ and HCM LGE− patients.