The purpose of this study is to explore the relationship between the ferroptosis-related gene zinc finger protein 36 (ZFP36) and the prognosis of osteosarcoma patients after surgery. Differential expression genes (DEGs) between osteosarcoma and normal tissues were screened using osteosarcoma chip data in GEO database. Based on the median expression quantity, ferroptosis DEGs were divided into high and low expression groups. Combined with its corresponding clinical survival data, the survival analysis of ferroptosis DEGs was carried out using the Survival package, and ferroptosis-related genes related to prognosis were identified. Next, the clinical data of 60 osteosarcoma patients treated in Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Zhongda Hospital and Nanjing Drum Tower Hospital from January 2011 to January 2016 were retrospectively analyzed. Immunohistochemistry and reverse transcription quantitative polymerase chain reaction (qRT-PCR) were used to detect gene expression in osteosarcoma. The Kaplan-Meier method and log rank test were used for univariate survival analysis, the Cox regression method was used for multivariate analysis, and the nomogram was constructed for internal verification on this basis. Immunohistochemical and reverse transcription quantitative PCR results showed that the expression of ZFP36 was mainly higher in cancer-adjacent tissues than in tumor tissues. There were significant differences in age, tumor location, Enneking stage, and tumor specific growth factor (TSGF) between the high and low expression groups of ZFP36 (P<0.05). The final study included 60 patients, of whom 23 patients died (mortality rate: 38.33%), and 37 patients survived (survival rate: 61.67%), with a median progression-free survival (PFS) of 32.5 months and a median overall survival (OS) of 77 months. The Cox multivariate analysis showed that distant metastasis and ZFP36 were independent risk factors affecting tumor progression (P=0.021 and P=0.006, respectively). Elevated ZFP36 can significantly prolong the OS and PFS of osteosarcoma patients. In internal verification, the Concordance index (C-index) of the nomogram was 0.7211 [95% confidence interval (CI): 0.6308-0.8115], and the prediction model had certain accuracy. Elevated ZFP36 can significantly prolong the OS and PFS in osteosarcoma patients. At the same time, ZFP36 could be used as a new predictive biomarker and novel therapeutic target for osteosarcoma patients. 2021 Annals of Translational Medicine. All rights reserved.