Purpose This study aims to further enhance a validated radiomics-based model for predicting pathologic complete response (pCR) after chemo-radiotherapy in locally advanced rectal cancer (LARC) for use in clinical practice. Methods A generalized linear model (GLM) to predict pCR in LARC patients previously trained in Europe and validated with an external inter-continental cohort (59 patients), was first examined with further 88 intercontinental patient datasets to assess its reproducibility; then new radiomics and clinical features, and validation methods were investigated to build a new model for enhancing the pCR prediction for patients admitted to our department. The patients were divided into training group (75%) and validation group (25%) according to their demographic. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to reduce the dimensionality of the extracted features of the training group and select the optimal ones; the performance of the reference GLM and enhanced models was compared through the area under curve (AUC) of the receiver operating characteristics. Results The value of AUC of the reference model was 0.831 (95% CI, 0.701-0.961), and 0.828 (95% CI, 0.700-0.956) in the original and new validation cohorts, respectively, showing a reproducibility in the applicability of the GLM model. Eight features were found to be significant with LASSO and used to establish an enhanced model. The AUC of the enhanced model of 0.926 (95% CI, 0.859-0.993) for training, and 0.926 (95% CI, 0.767-1.00) for the validation group shows better performance than the reference model. Conclusions The GLM model shows good reproducibility in predicting pCR in LARC; the enhanced model has the potential to improve prediction accuracy and may be a candidate in clinical practice.