Glucocorticoid-induced osteoporosis (GIOP) is a public health problem that needs urgently to be resolved, and oxidative stress is closely related to osteogenic impairment. TP53-induced glycolysis and apoptosis regulator (TIGAR) contributes to the occurrence and development of various diseases by reducing reactive oxygen species (ROS). However, it is unknown whether and how TIGAR plays a regulatory role in GIOP. The aim of the present study is to investigate the role of TIGAR in osteogenic differentiation and the underlying molecular mechanism. We explored the protective role and mechanism of TIGAR on osteogenic differentiation and GIOP by using the TIGAR overexpression plasmid and siRNA in vitro, and by constructing systemic TIGAR overexpression (TG-TIGAR) mice in vivo, respectively. In conclusion, our study clarified that TIGAR promotes osteogenic differentiation and improves GIOP by upregulating autophagy-nuclear factor erythroid-2 related factor (Nrf2)-ROS pathway, suggesting that TIGRA may be a potential therapeutic target for GIOP treatment.