Background: Osteosarcoma is the most general bone malignancy that mostly affects children and adolescents. Numerous stem cell-related genes have been founded in distinct forms of cancer. This study aimed at identifying a stem cell-related gene model for the expected assessment of the prognosis of osteosarcoma patients.Methods: We obtained the genes expression data and relevant clinical materials from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. We identified differentially expressed genes (DEGs) from the GEO dataset, whereas prognostic stem cell-related genes were obtained from the TARGET database. Subsequently, univariate, LASSO and multivariate Cox regression analyses were applied to establish the stem cell-related signature. Finally, the prognostic value of the signature was validated in the GEO dataset.Results: Twenty-five genes were prognostic ferroptosis-related DEGs. Consequently, we identified eight stem cell-related genes as a signature of prognosis of osteosarcoma patients. Then, the Kaplan–Meier (K-M) curve, the AUC value of ROC, and Cox regression analysis verified that the eight stem cell-related gene model were a new and substantial prognostic marker independent of other clinical traits. Moreover, the nomogram on the foundation of risk score and other clinical traits was established for predicting the survival rate of osteosarcoma patients. Biological function analyses displayed that tumor related pathways were affluent.Conclusion: The expression level of stem cell-related genes offers novel prognostic markers as well as underlying therapeutic targets for the therapy and prevention of osteosarcoma.