The receptor activator of the nuclear factor kappa B ligand (RANKL) is the therapeutic target of denosumab. In this study, we evaluated whether radiomics signature and machine learning analysis can predict RANKL status in spinal giant cell tumors of bone (GCTB). This retrospective study consisted of 107 patients, including a training set (n = 82) and a validation set (n = 25). Kaplan-Meier survival analysis was used to validate the prognostic value of RANKL status. Radiomic feature extraction of three heterogeneous regions (VOI^entire, VOI^edge, and VOI^core) from pretreatment CT were performed. Followed by feature selection using Selected K Best and least absolute shrinkage and selection operator (LASSO) analysis, three classifiers (random forest (RF), support vector machine, and logistic regression) were used to build models. The area under the curve (AUC), accuracy, F1 score, recall, precision, sensitivity, and specificity were used to evaluate the models’ performance. Classification of 75 patients with eligible follow-up based on RANKL status resulted in a significant difference in progression-free survival (p = 0.035). VOI^core-based RF classifier performs best. Using this model, the AUCs for the training and validation cohorts were 0.880 and 0.766, respectively. In conclusion, a machine learning approach based on CT radiomic features could discriminate prognostically significant RANKL status in spinal GCTB, which may ultimately aid clinical decision-making.