Artemisia annua L. is a well-known traditional herb medicine, and possesses antioxidant, antiobesity and antiosteoporosis properties. This paper aimed to explore the role and mechanism of Artemisia annua L. on glucocorticoid-induced osteoporosis (GIOP). Artemisia annua L. extract (AE) improved bone mineral density (BMD) and micro-architectural parameters in GIOP mice femur. Biological indicators showed that AE protected bone formation and inhibited fat formation in GIOP mice, and the potential mechanism was regulating oxidative stress (OS) via promoting the nuclear expression of Nrf2. To further investigate the mechanism of AE on GIOP, MC3T3-E1 cells injured by dexamethasone (DEX) were used for in vitro study. AE promoted proliferation and mineralization, upregulated the expression of Runx2, and downregulated the expression of PPARγ in DEX-injured MC3T3-E1 cells. In addition, AE reduced the level of oxidative factors and promoted the level of antioxidant enzymes in DEX-injured MC3T3-E1 cells. Western blot showed that AE activated the PGC-1α/Nrf2 pathway, which may be the potential mechanism of AE playing antioxidant role. Furthermore, PGC-1α or Nrf2 knockdown by siRNA reversed the antioxidant effect of AE. These results revealed that AE exerts anti-GIOP effects via egulating bone-fat metabolism via regulating PGC-1α/Nrf2-mediated OS.