Abstract This study aims to comprehensively evaluate the clinical utility of five diffusion models, including conventional mono-exponential (Mono), intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), stretched exponential (SEM), and continuous-time random-walk (CTRW), for preoperatively predicting of breast lesion pathology, prognostic biomarkers, and molecular subtypes. We retrospectively analyzed 132 patients with pathologically verified breast lesions (41 benign and 91 malignant) who underwent a full protocol preoperative breast MRI protocol, including a diffusion-weighted imaging (DWI) sequence with nine b values (0 to 2000 s/mm2) on a 3.0T MR scanner. The diffusion parameters from each model—Mono (ADC), IVIM (D, D*, f), DKI (MD, MK), SEM (DDC, α) and CTRW (Dm, α, β)—were quantitatively calculated and compared between benign and malignant breast lesions, as well as across different prognostic biomarker statuses in breast cancer, using Mann–Whitney U-tests. For molecular subtypes comparisons, we employed the Kruskal-Wallis test followed by Bonferroni. All parameters, except IVIM-D*, significantly differentiated benign from malignant lesions. Notably, IVIM-D and DKI-MK values were significantly different between estrogen receptor (ER)-positive and ER-negative tumors. Progesterone receptor (PR)-positive cancers exhibited lower Mono-ADC, IVIM-D, DKI-MD, SEM-DDC, CTRW-Dm, and CTRW-α values, alongside higher DKI-MK value compared to PR-negative cancers (p