The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray expression profiles of normal samples, and metastatic and non‑metastatic OS samples. The GSE9508 gene expression profile was downloaded from the Gene Expression Omnibus database, which included 11 human metastatic OS samples, seven non‑metastatic OS samples and five normal samples. Pretreatment of the data was performed using the BioConductor package in R language, and the differentially expressed genes (DEGs) were identified by a t‑test. Furthermore, function and pathway enrichment analyses of the DEGs were conducted using a molecule annotation system. A differential co‑expression network was also constructed, and the submodules were screened using MCODE in Cytoscape. A total of 965 genes were identified as DEGs in metastatic OS. The DEGs were shown to participate in the regulation of DNA‑dependent transcription, the composition of the nucleus, cytoplasm and membrane, and protein and nucleotide binding. Furthermore, the screened DEGs were significantly associated with the ribosome, axon guidance and the cytokine‑cytokine receptor interaction pathway. Certain hub genes were identified in the constructed differential co‑expression network, including matrix metalloproteinase 1 (MMP1), smoothened (SMO), ewing sarcoma breakpoint region 1 (EWSR1) and fasciculation and elongation protein ζ‑1 (FEZ1). Brain selective kinase 2 (BRSK2) and aldo‑keto reductase family 1 member B10 (AKRIB10) were present in the screened submodules. The results of the present study suggest that genes, including MMP1, SMO, EWSR1, FEZ1, BRSK2 and AKRIB10, may be potential targets for the diagnosis and treatment of metastatic OS.