Recently, many kinds of microRNAs (miRNAs) have been found to play a critical role in progression of osteosarcoma (OS). miR-217 was reported to function as a tumor suppressor in a number of human cancers but its precise mechanism to exert the suppressive role remains to be investigated. In this study, we found that miR-217 was downregulated in OS tissues and its downregulation predicts poor overall survival of OS patients. Importantly, we found that a lower expressed miR-217 in OS cell lines inhibited the cell proliferation and invasion in vitro. By bioinformatic analysis, we found that miR-217 targeted the SET Domain-Containing Protein 8 (SETD8), and there was a negative correlation between them in OS tissues. Furthermore, we found that miR-217 abolished the stimulation effect of SETD8 on cell proliferation and invasion. Taken together, our data provide solid evidence that miR-217 functions as tumor suppressor in OS, and its tumor-suppressive effect is exerted through interaction with SETD8.