OBJECTIVE: The aim of this study was to develop and validate a deep learning radiomics (DLR) model based on longitudinal ultrasound data and clinical features to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: Between January 2018 and June 2023, 312 patients with histologically confirmed breast cancer were enrolled and randomly assigned to a training cohort (n = 219) and a test cohort (n = 93) in a 7:3 ratio. Next, pre-NAC and post-treatment 2-cycle ultrasound images were collected, and radiomics and deep learning features were extracted from NAC pre-treatment (Pre), post-treatment 2 cycle (Post), and Delta (pre-NAC-NAC 2 cycle) images. In the training cohort, to filter features, the intraclass correlation coefficient test, the Boruta algorithm, and the least absolute shrinkage and selection operator (LASSO) logistic regression were used. Single-modality models (Pre, Post, and Delta) were constructed based on five machine-learning classifiers. Finally, based on the classifier with the optimal predictive performance, the DLR model was constructed by combining Pre, Post, and Delta ultrasound features and was subsequently combined with clinical features to develop a combined model (Integrated). The discriminative power, predictive performance, and clinical utility of the models were further evaluated in the test cohort. Furthermore, patients were assigned into three subgroups, including the HR+/HER2-, HER2+, and TNBC subgroups, according to molecular typing to validate the predictability of the model across the different subgroups. RESULTS: After feature screening, 16, 13, and 10 features were selected to construct the Pre model, Post model, and Delta model based on the five machine learning classifiers, respectively. The three single-modality models based on the XGBoost classifier displayed optimal predictive performance. Meanwhile, the DLR model (AUC of 0.827) was superior to the single-modality model (Pre, Post, and Delta AUCs of 0.726, 0.776, and 0.710, respectively) in terms of prediction performance. Moreover, multivariate logistic regression analysis identified Her-2 status and histological grade as independent risk factors for NAC response in breast cancer. In both the training and test cohorts, the Integrated model, which included Pre, Post, and Delta ultrasound features and clinical features, exhibited the highest predictive ability, with AUC values of 0.924 and 0.875, respectively. Likewise, the Integrated model displayed the highest predictive performance across the different subgroups. CONCLUSION: The Integrated model, which incorporated pre-NAC treatment and early treatment ultrasound data and clinical features, accurately predicted pCR after NAC in breast cancer patients and provided valuable insights for personalized treatment strategies, allowing for timely adjustment of chemotherapy regimens.