Background: This research focused on evaluating the utility of multimodal radiomics integrated with machine learning to predict pathological complete response (pCR) in a prospective cohort of esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant immunochemotherapy (nICT). Methods: We retrospectively analyzed prospectively collected trial data from 66 ESCC patients. Radiomic features were extracted from computed tomography (CT) and magnetic resonance imaging (MRI) images. Four machine learning algorithms—Random Forest (RF), logistic regression, Support Vector Machine, and Extreme Gradient Boosting (XGBoost)—were applied with leave-one-out cross-validation to predict pCR after nICT. The predictive performance of the models was evaluated using receiver operating characteristic curve analysis. Results: In total, 851 features were identified. Among the four machine learning algorithms, the XGBoost machine learning method demonstrated the best model performance across CT, MRI, and clinical feature-based models. Furthermore, the integrated model demonstrated superior performance compared to individual models based solely on CT, MRI, or clinical features across all machine learning algorithms. Among these, the XGboost-based integrated model achieved the highest performance on the test set, with an AUC of 0.961, a TPR of 84.2%, a TNR of 95.7%, a PPV 88.9% of and a NPV of 93.8%. Decision curve analysis validated the model’s robust clinical utility, with calibration curves demonstrating strong concordance between predicted and observed therapeutic responses. Conclusions: The study demonstrates the potential for predicting pCR in patients with ESCC treated with standardized neoadjuvant chemotherapy and PD-1 inhibitors using machine learning methods that integrate multimodal CT and MRI images with clinical features.