Background A non-invasive tool for tumor regression grade (TRG) evaluation is urgently needed for gastric cancer (GC) treated with neoadjuvant chemotherapy (NAC). Purpose To develop and validate a radiomics signature (RS) to evaluate TRG for locally advanced GC after NAC and assess its prognostic value. Material and Methods A total of 103 patients with GC treated with NAC were retrospectively recruited from April 2018 to December 2019 and were randomly allocated into a training cohort (n = 69) and a validation cohort (n = 34). Delineation was performed on both mixed and iodine-uptake images based on dual-energy computed tomography (DECT). A total of 4094 radiomics features were extracted from the pre-NAC, post-NAC, and delta feature sets. Spearman correlation and the least absolute shrinkage and selection operator were used for dimensionality reduction. Multivariable logistic regression was used for TRG evaluation and generated the optimal RS. Kaplan–Meier survival analysis with the log-rank test was implemented in an independent cohort of 40 patients to validate the prognostic value of the optimal RS. Results Three, five, and six radiomics features were finally selected for the pre-NAC, post-NAC, and delta feature sets. The delta model demonstrated the best performance in assessing TRG in both the training and the validation cohorts (AUCs=0.91 and 0.76, respectively; P>0.1). The optimal RS from the delta model showed a significant capability to predict survival in the independent cohort ( P<0.05). Conclusion Delta radiomics based on DECT images serves as a potential biomarker for TRG evaluation and shows prognostic value for patients with GC treated with NAC.