Aims To develop and validate a model for predicting major pathological response to neoadjuvant chemotherapy (NAC) in advanced gastric cancer (AGC) based on a machine learning algorithm. Method A total of 221 patients who underwent NAC and radical gastrectomy between February 2013 and September 2020 were enrolled in this study. A total of 144 patients were assigned to the training cohort for model building, and 77 patients were assigned to the validation cohort. A major pathological response was defined as primary tumor regressing to ypT0 or T1. Radiomic features extracted from venous-phase computed tomography (CT) images were selected by machine learning algorithms to calculate a radscore. Together with other clinical variables selected by univariate analysis, the radscores were included in a binary logistic regression analysis to construct an integrated prediction model. The data obtained for the validation cohort were used to test the predictive accuracy of the model. Result A total of 27.6% (61/221) patients achieved a major pathological response. Five features of 572 radiomic features were selected to calculate the radscores. The final established model incorporates adenocarcinoma differentiation and radscores. The model showed satisfactory predictive accuracy with a C-index of 0.763 and good fitting between the validation data and the model in the calibration curve. Conclusion A prediction model incorporating adenocarcinoma differentiation and radscores was developed and validated. The model helps stratify patients according to their potential sensitivity to NAC and could serve as an individualized treatment strategy-making tool for AGC patients.