Osteosarcoma is a primary malignant tumor found mainly in teenagers and young adults. Patients have very little long-term survival.MYCcontrols tumor initiation and progression by regulating the expression of its target genes; thus, constructing a risk signature of osteosarcomaMYCtarget gene set will benefit the evaluation of both treatment and prognosis. In this paper, we used GEO data to download the ChIP-seq data ofMYCto obtain theMYCtarget gene. Then, a risk signature consisting of 10MYCtarget genes was developed using Cox regression analysis. The signature indicates that patients in the high-risk group performed poorly. After that, we verified it in the GSE21257 dataset. In addition, the difference in tumor immune function among the low- and high-risk populations was compared by single sample gene enrichment analysis. Immunotherapy and prediction of response to the anticancer drug have shown that the risk signature of theMYCtarget gene set was positively correlated with immune checkpoint response and drug sensitivity. Functional analysis has demonstrated that these genes are enriched in malignant tumors. Finally,STX10was selected for functional experimentation.STX10silence has limited osteosarcoma cell migration, invasion, and proliferation. Therefore, these findings indicated that theMYCtarget gene set risk signature could be used as a potential therapeutic target and prognostic indicator in patients with osteosarcoma.