Objective: This study aimed to investigate the impact of Dickkopf 2 (DKK2) on the progression of oral squamous cell carcinoma (OSCC) and explore its role in the PI3K/AKT signaling transduction pathway. Materials and Methods: The study initially examined the expression of the DKK2 gene in OSCC tissues and normal tissues. Simultaneously, the expression of DKK2 in HOK cells and OSCC cells was verified, and changes in DKK2 expression under hypoxic conditions were detected. DKK2 overexpression and knockdown were performed in SCC-15 and CAL-27 cells. Subsequently, the effects of DKK2 on the proliferation, migration and invasion of OSCC were detected. Western blotting was employed to detect the expression of key proteins in the DKK2/PI3K/AKT signaling axis before and after transfection, and further explore the relevant molecular mechanisms. Results: Compared to normal tissues, DKK2 expression was elevated in OSCC tissues. The expression of DKK2 in the SCC-15 and CAL-27 cell lines was higher than that in HOK cells, and hypoxic conditions could promote DKK2 expression. DKK2 overexpression promoted cell proliferation, migration, and invasion, while DKK2 knockdown inhibited these processes. DKK2 overexpression activated the PI3K/AKT pathway, while DKK2 knockdown suppressed this pathway. Conclusion: This study suggests that hypoxic conditions enhance the expression of DKK2 in OSCC. DKK2 regulates the proliferation, migration, and invasion of OSCC through the PI3K/AKT signaling pathway.