Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1), a novel identified long noncoding RNA (lncRNA), has been suggested to serve as oncogene in multiple cancers. However, the functional involvement of OIP5-AS1 in oral squamous cell carcinoma (OSCC) was still unknown. The aims of this study were to investigate the functional role of OIP5-AS1 in OSCC and explore its potential mechanism. We found that OIP5-AS1 was up-regulated in OSCC tissues compared with adjacent non-tumor tissues. Loss-of-function experiments revealed that OIP5-AS1 knockdown significantly inhibited OSCC cell proliferation, migration and invasion in vitro, and retarded tumor growth in vivo. Mechanistically, OIP5-AS1 serves as a competing endogenous RNA of miR-338-3p and modulates the expression of neuropilin1 (NRP1), which has been identified as a downstream target gene of miR-338-3p in OSCC. Moreover, downregulation of miR-338-3p or overexpression of NRP1 partly reversed the inhibitory effect of OIP5-AS1 depletion on cell proliferation, migration and invasion. The current results provide evidences for the role of OIP5-AS1 in promoting OSCC progression by regulating miR-338-3p/NRP1 axis and suggest OIP5-AS1 as a potential therapy target for OSCC.