Most malignant neoplasms of the oral cavity are oral squamous cell carcinoma (OSCC), which is a type of highly malignant tumor with a propensity for forming distant metastases. Trophoblast cell surface antigen 2 (TROP2) is a transmembrane protein that is overexpressed in several types of tumor cells, although its role and regulatory mechanism in OSCC have not been determined. The aim of the present study was to examine the effects of TROP2 in human OSCC cell lines. The present study demonstrated that TROP2 protein expression was upregulated in OSCC cell lines. Transfection of short hairpin RNA (shRNA) targeting TROP2 (sh?TROP2) reduced cell proliferation, migration and invasion of OSCC cell lines, whereas overexpression of TROP2 increased proliferation, migration and invasion. sh?TROP2 transfection in OSCC cell lines inhibited tumor growth in OSCC mouse models. Furthermore, TROP2 expression activated the phosphoinositide 3?kinase (PI3K)/Akt signaling pathway in human OSCC cells. These results suggest that TROP2 induces cell growth, migration and invasion through activation of the PI3K/Akt signaling pathway in OSCC cells.