Abstract Background It has been believed that traditional handcrafted radiomic features extracted from magnetic resonance imaging (MRI) of tumors are normally shallow and low-ordered. Recent advancement in deep learning technology shows that the high-order deep radiomic features extracted automatically from tumor images can capture tumor heterogeneity in a more efficient way. We hypothesize that MRI-based deep radiomic phenotypes have significant associations with molecular profiles of breast cancer tumors. We aim to identify deep radiomic features (DRFs) from MRI, evaluate their significance in predicting breast cancer (BC) clinical characteristics and explore their associations with multi-level genomic factors. Methods A denoising autoencoder was built to retrospectively extract 4,096 DRFs from 110 BC patients’ MRI. Visualization and clustering were applied to these DRFs. Linear Mixed Effect models were used to test their associations with multi-level genomic features (GFs) (risk genes, gene signatures, and biological pathway activities) extracted from the same patients’ mRNA expression profile. A Least Absolute Shrinkage and Selection Operator model was used to identify the most predictive DRFs for each clinical characteristic (tumor size (T), lymph node metastasis (N), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status). Results Thirty-six conventional radiomic features (CRFs) for 87 of the 110 BC patients provided by a previous study were used for comparison. More than 1,000 DRFs were associated with the risk genes, gene signatures, and biological pathways activities (adjusted P-value < 0.05). DRFs produced better performance in predicting T, N, ER, PR, and HER2 status (AUC > 0.9) using DRFs. These DRFs showed significant powers of stratifying patients, linking to relevant biological and clinical characteristics. As a contrast, only eight risk genes were associated with CRFs. The RFs performed worse in predicting clinical characteristics than DRFs. Conclusions The deep learning-based auto MRI features perform better in predicting BC clinical characteristics, which are more significantly associated with GFs than traditional semi-auto MRI features. Our radiogenomic approach for identifying MRI-based imaging signatures may pave potential pathways for the discovery of genetic mechanisms regulating specific tumor phenotypes and may enable a more rapid innovation of novel imaging modalities, hence accelerating their translation to personalized medicine.