Osteosarcoma (OS) is the most frequent type of primitive malignant bone tumor with a poor prognosis due to distant metastasis. Our previous studies have demonstrated that IRX2 is overexpressed and is important in cell proliferation and invasion. However, the molecular mechanisms underlying the IRX2‑dependent regulation of OS progression remains to be elucidated. In the present study, the effects of IRX2 on the upregulation of MMP2 and VEGF in OS were determined by western blotting, and the underlying molecular mechanisms were elucidated. These findings provided data suggesting that IRX2 modulates the expression levels of MMP2 and VEGF in an AKT‑dependent manner. The overexpression of IRX2 promoted the activation of PI3K/Akt and increased the proliferation and invasiveness of the OS cell lines as shown by CCK8 and invasion assays. Notably, interruption of the AKT pathway by treatment with LY294002, a specific PI3K inhibitor, attenuated IRX2‑induced cell proliferation and invasive ability, and the upregulation of MMP2 and VEGF. The results of the present study suggested that inhibition of the IRX2‑mediated AKT signaling pathway may be a suitable therapeutic target for the treatment of OS.