Osteosarcoma (OS) is the most common bone-derived tumor, and chemoresistance is a pivotal factor in the poor prognosis of patients with OS. Ferroptosis, as an emerging modality of regulated cell death, has demonstrated potential value in tumor chemoresistance studies. Through the gene expression omnibus database in conjunction with the FerrDb database, we identified novel ferroptosis-related differentially expressed genes (DEGs) involving chemoresistance in OS patients. Subsequently, enrichment analysis, protein-protein interaction network analysis and survival analysis were performed sequentially to recognize the hub genes and ultimately to construct a predictive model. The model constructed from the TARGET database was exhibited in a nomogram and assessed by calibration curves. The prognostic value of the model and hub genes was validated separately by an independent cohort. Twenty-two ferroptosis-related DEGs were identified, including 16 up-regulated and 6 down-regulated. Among them, expressions of CBS, COCS1, EGFR, as hub genes, were significantly associated with the prognosis of OS patients and were evidenced as independent prognostic factors. An efficient prognostic model covering hub gene expressions and clinical variables was developed and validated. Combining the results of hub genes in differential analysis, the actions of hub genes in ferroptosis, and the prognostic relevance of hub genes in patients, we revealed that CBS, SOCS1 and EGFR might play essential roles in OS and its chemoresistance with potential research and clinical value.© 2022. The Author(s).