RSF1 (HBXAP), is a member of ATP-dependent chromatin remodeling factor. Dysregulated RSF1 has been reported to be related to tumor progression. However, the function of RSF1 in osteosarcoma (OS) remains unclear. In this study, we showed that RSF1 expression was upregulated in OS cells. RSF1 inhibition suppressed OS cell proliferation and invasion. We further showed that MAPK/Erk signaling pathway was inactivated by RSF1 suppression. In addition, RSF1 was identified as a direct target of miR-193a-3p. Clinically, RSF1 was increased and associated with advanced clinical features and poor overall survival of OS patients. MiR-193a-3p expression was decreased and associated with advanced clinical features and poor overall survival of OS patients. In addition, we found that miR-193a-3p was negatively correlated with RSF1 expression in OS tissues. Moreover, our data showed that XIST could function as competing endogenous RNA to repress miR-193a-3p, which regulated its downstream target RSF1. In conclusion, our findings demonstrated that the XIST/miR-193a-3p/RSF1 axis might contribute to the progression and act as a therapeutic target of OS patients.