Long noncoding RNAs (lncRNAs) have been verified to participate in various types of malignant tumors, including osteosarcoma (OS), which is the most common primary bone tumor with outstanding morbidity. Although an increasing number of lncRNAs have been reported to mediate the occurrence of OS, the potential mechanisms are still unclear. This study intends to uncover the mechanism by which lncRNA LINC01133 functions as an miRNA sponge to mediate OS tumorigenicity. In this study, we found that the expression level of LINC01133 was statistically upregulated in OS tumor tissue and cell lines compared to noncancerous tissues and a normal human osteoplastic cell line. LINC01133 silencing could also observably suppress the proliferation, migration, and invasion of OS cells (HOS and U2-OS). Bioinformatics analysis predicted that LINC01133 specifically targeted miR-422a, which was validated by dual-luciferase reporter assay. Furthermore, functional experiments revealed that miR-422a played a tumor-suppressive role in OS progression and could effectively reverse the function of LINC01133. In summary, our study discovered that lncRNA LINC01133 aggravates the proliferation, migration, and invasion of OS by sponging miR-422a, which provides a novel insight in the tumorigenesis of OS.