The present study aimed to understand the molecular mechanisms underlying osteosarcoma metastasis. Microarray dataset GSE49003 was downloaded from the Gene Expression Omnibus database and used for analysis. Raw expression data were preprocessed using the preprocessCore, impute and aggregate packages in R. Differentially expressed genes (DEGs) between metastatic and non‑metastatic osteosarcoma cell lines were screened using the limma package following exclusion of DEGs with a higher significance in intra‑groups compared with inter‑groups using the genefilter package. Enrichment analysis was performed on DEGs using TargetMine, followed by identification of transcription factors (TFs) and microRNAs (miRNAs). Regulatory networks were constructed using Cytoscape software. A total of 248 upregulated and 208 downregulated genes were obtained. The upregulated genes were significantly enriched in the following pathways: Downregulation of transforming growth factor β (TGF‑β) receptor signaling and TGF‑β receptor signaling activates SMADs; these upregulated genes included protein phosphatase 1, regulatory subunit 15A, transforming growth factor, β receptor II and ubiquitin carboxyl‑terminal hydrolase L5. In addition, some upregulated genes were enriched in lung cancer disease ontology, including epidermal growth factor receptor (EGFR), insulin‑like growth factor 2 mRNA binding protein 3 (IGF2BP3), runt‑related transcription factor 3 (RUNX3) and secreted frizzled‑related protein 1 (SFRP1). Conversely, the downregulated genes were significantly enriched in extracellular matrix‑associated pathways or functions, such as collagen, type XII, α 1; collagen, type I, α 1; collagen, type IV, α 1; and collagen, type V, α 1. In addition, some downregulated genes were significantly enriched in the TGF‑β signaling pathway, including bone morphogenetic protein 4, inhibitor of DNA binding 3 and SMAD family member 6. A total of 10 TFs and 84 miRNAs (e.g. miR-21-5p) were deemed to be associated with DEGs. In conclusion, DEGs enriched in the downregulation of TGF‑β receptor signaling, TGF‑β receptor signaling activates SMADs and TGF‑β signaling pathways, as well as the extracellular matrix may be implicated in the progression of osteosarcoma metastasis. Dysregulated EGFR, IGF2BP3, RUNX3 and SFRP1 may contribute to the metastasis of osteosarcoma to the lungs. In addition, screened TFs and miR-21-5p may be associated with metastasis via target genes.