Opa-interacting protein 5 antisense RNA1 (OIP5-AS1) has been demonstrated to facilitate proliferation, metastasis and resistance to treatments in various types of cancers. Nevertheless, the exact mechanisms underlying the roles of OIP5-AS1 in osteosarcoma(OS) drug resistance have not yet been clearly elucidated. Therefore, we sought to investigate the functional involvement of OIP5-AS1 in osteosarcoma. Our results indicated that OIP5-AS1 was dramatically up-regulated in osteosarcoma drug-resistant tissues and cells in comparison with drug-sensitive tissues and cells. Also, the knockdown of OIP5-AS1 was found to have decreased doxorubicin resistance of OS cells. Further analyses revealed that OIP5-AS1 operated as a competitor for endogenous RNA of miR-137-3p as well as regulated pleiotrophin(PTN) expression, which has been reported to be an oncogene in OS in previous research. Furthermore, the loss of miR-137-3p or alternatively, the gain of PTN, both resulted in the abolishment of the inhibitory role of OIP5-AS1 silencing the proliferative activity. Our analyses indicated and helped to determine the role of OIP5-AS1 in contributing to tumorigenesis of osteosarcoma via the miR-137-3p/PTN axis and, therefore outlining its potential for use as a therapeutic target against this cancer.