Background: The purpose of this study was to investigate and validate multiparametric magnetic resonance imaging (MRI)-based machine learning classifiers for early identification of poor responders after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). Methods: Patients with LARC who underwent nCRT were included in this retrospective study (207 patients). After preprocessing of multiparametric MRI, radiomics features were extracted and four feature selection methods were used to select robust features. The selected features were used to build five machine learning classifiers, and 20 (four feature selection methods × five machine learning classifiers) predictive models for the screening of poor responders were constructed. The predictive models were evaluated according to the area under the curve (AUC), F1 score, accuracy, sensitivity, and specificity. Results: Eighty percent of all predictive models constructed achieved an AUC of more than 0.70. A predictive model using a support vector machine classifier with the minimum redundancy maximum relevance (mRMR) selection method followed by the least absolute shrinkage and selection operator (LASSO) selection method showed superior prediction performance, with an AUC of 0.923, an F1 score of 88.14%, and accuracy of 91.03%. The predictive performance of the constructed models was not improved by ComBat compensation. Conclusions: In rectal cancer patients who underwent neoadjuvant chemoradiotherapy, machine learning classifiers with radiomics features extracted from multiparametric MRI were able to accurately discriminate poor responders from good responders. The techniques should provide additional information to guide patient-tailored treatment.