Glycoprotein non‑metastatic melanoma protein B (GPNMB) is a glycoprotein that is highly expressed in various types of cancer, including osteosarcoma. However, its cellular functions and related mechanisms in osteosarcoma remain unclear. In the present study, a higher GPNMB mRNA level was observed in osteosarcoma tissues, than in adjacent non‑cancerous tissues. In addition, upregulation of the GPNMB mRNA and protein level was detected in the osteosarcoma cells SaOS2, 143B, MG63 and U2OS using western blot analysis and qPCR. Following transfection with GPNMB siRNA, the proliferation, migration and invasion of MG63 and U2OS cells were assessed using MTT and Transwell assays. The knockdown of GPNMB markedly inhibited the proliferation and metastasis of MG63 and U2OS cells. GPNMB silencing inhibited the activation of PI3K/Akt/mTOR signaling in MG63 and U2OS cells. PI3K/AKT activator insulin‑like growth factor‑1 (IGF‑1) significantly activated the PI3K/Akt/mTOR signaling and reversed the suppressive effects of GPNMB silencing. IGF‑1 counteracted the inhibitory effects of GPNMB silencing on the proliferation and metastasis of the MG63 and U2OS cells. In conclusion, we provided evidence that GPNMB silencing regulated the proliferation and metastasis of osteosarcoma cells by suppressing the PI3K/Akt/mTOR signaling pathway. Thus, GPNMB may be a potential therapeutic target for osteosarcoma treatment.