Cisplatin-based chemotherapy has been found to improve the prognosis of patients with tongue squamous cell carcinoma (TSCC), the most common oral cancer with a poor prognosis. Chemoresistance to cisplatin appears to be an important clinical problem for cisplatin-based TSCC chemotherapy. Long noncoding RNAs (lncRNAs) play important roles in regulating tumor cells' sensitivity to chemotherapeutic agents. A recent study has shown that the expression of lncRNA UCA1 is significantly enhanced in TSCCs, suggesting that UCA1 may play a role in TSCC progression. In the present study, we explored the effects and the underlying mechanisms of UCA1 on cisplatin chemosensitivity/chemoresistance and apoptosis in TSCC cells. Transient transfection of siRNA was used to knock down UCA1 in human TSCC cell lines CAL 27 and SCC-9, where UCA1 was highly overexpressed compared to normal human tongue tissues. Knockdown of UCA1 markedly increased cisplatin-induced caspase 3 activity and apoptosis in CAL 27 and SCC-9 cells. On the other hand, it decreased cisplatin-induced phosphatidylinositol 3-kinase (PI3K) activity and activation phosphorylation of Akt. UCA1 knockdown resulted in one magnitude decrease in the half maximal inhibitory concentration (IC50) of cisplatin in CAL 27 and SCC-9 cells, from 8.9 mM and 20.7 mM down to 0.6 mM and 1.7 mM, respectively. In conclusion, this study has shown that UCA1 knockdown markedly increased cisplatin-induced apoptosis and chemosensitivity in TSCC cells, likely through inhibiting cisplatin-activated PI3K/Akt signaling. It provides new insights into the functional role of UCA1 in cancer cells and suggests that UCA1 knockdown could be a new strategy to increase cisplatin chemosensitivity and thereby improve the therapeutic outcomes of cisplatin-based chemotherapy for TSCC.