Increasing evidence suggest that pleckstrin‑2 (PLEK2) acts as an oncogene in several malignancies. The present study aimed to investigate the effects of PLEK2 on osteosarcoma (OS) tumorigenesis and metastasis. PLEK2 expression in OS was analyzed via bioinformatics, reverse transcription‑quantitative PCR, western blot and immunohistochemistry analyses. The Cell Counting Kit‑8 (CCK‑8), colony formation and EdU assays were performed to assess the role of PLEK2 in OS cell proliferation. The pro‑metastatic effects of PLEK2 were assessed via the Transwell and wound healing assays. In addition, the PLEK2 downstream pathway was analyzed via bioinformatics analysis and verified via western blot analysis. The results demonstrated that PLEK2 expression was upregulated in both OS cell lines and specimens. The results of the CCK‑8, colony formation and EdU assays demonstrated that PLEK2 promoted OS cell proliferation in vitro. The in vivo experiments further demonstrated that PLEK2 knockdown significantly suppressed OS growth. In addition, the Transwell and wound healing assays indicated that PLEK2 promoted OS invasiveness in vitro, which was induced by the activation of the epithelial‑to‑mesenchymal transition process. Bioinformatics analysis revealed that PLEK2 can activate the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, which was verified via western blot analysis. Taken together, the results of the present study suggest that PLEK2 may play a tumor‑promoting role in OS via the PI3K/AKT signaling pathway.