Purpose: To investigate the diagnostic value of multi-model high-resolution diffusion-weighted MR imaging (DWI) in breast lesions, with a comparison of simultaneous multi-slice readout-segmented echo-planar imaging (SMS rs-EPI) and single-shot EPI (ss-EPI). Materials and Methods: This retrospective study was approved by the institutional ethics committee and included 120 patients with 122 breast lesions (25 benign and 97 malignant). All patients underwent breast DWI with multi-b values (0, 50, 100, 200, 400, 800, 1200, and 2000 s/mm2) based on both SMS rs-EPI and ss-EPI on a 3.0 T MR scanner. Quantitative DWI-derived parameters including ADC, MK, MD, D, D*, and f were calculated based on mono-exponential (Mono), intravoxel incoherent motion (IVIM), diffusion kurtosis (DKI) models. Meanwhile, both DWI sequences were qualitatively evaluated with respect to overall image quality, lesion conspicuity, image artifact, geometric distortion, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and lesion contrast. The differences in DW-derived parameters, image quality, and diagnostic performance were statistically compared between SMS rs-EPI and ss-EPI groups. Results: The SMS rs-EPI produced higher Contrast, CNR and lower SNR than ss-EPI (p < 0.01). The image quality of SMS rs-EPI was superior to ss-EPI either in subjective or objective evaluation. There was no significant difference between the SMS rs-EPI and ss-EPI for either MD or the D* (p > 0.05). However, the MK and f between the two sequences showed significant differences (p < 0.05). Spearman's correlation coefficient displayed good linear correlation for MK values (r = 0.73, 95% CI 0.617-0.857), MD values (r = 0.88, 95% CI 0.814-0.926), ADC values (r = 0.93, 95% CI 0.869-0.948) and D values (r = 0.93, 95% CI 0.856-0.948) between SMS rs-EPI and ss-EPI. Spearman's correlation coefficient for f values (r = 0.25, 95% CI 0.226-0.559) and D* values (r = 0.22, 95% CI 0.025-0.348) were fair and no correlation between the two sequences. MK values have the highest diagnostic value in differentiating benign and malignant breast lesions. Conclusions: High-resolution multi-model DWI based on SMS rs-EPI technique can provide superior image quality and lesion characterization, with comparable diagnostic performance as compared with ss-EPI DWI in differentiating benign and malignant breast lesions. Of different DWI-derived parameters, MK values showed the best diagnostic performance.