Objective To observe the effects of the Qiang Gu Kang Wei Extraction on bone apoptosis and endoplasmic reticulum stress in tail suspension rats, and to explore the mechanism of the extraction in preventing bone loss in simulated weightlessness. Methods 60 SD rats were randomly divided into control group, simulated weightlessness group, Qiang Gu Kang Wei Extraction group, alendronate sodium group and Gushukang granule group, with 12 rats in each group. The tail suspension was used to simulate weightlessness for 28 days. The control group and the simulated weightlessness group were given equal volume of normal saline, while the other three groups were tail suspended and given 2.4 g/kg Qiang Gu Kang Wei Extraction, 0.007 g/kg alendronate sodium, and 0.26 g/kg Gushukang granule by gavage, respectively. After 4 weeks of intragastric administration, rats were sacrificed, and the apoptosis of bone cells was detected by TUNEL. RT-PCR detected transcription levels of protein kinase R-like endoplasmic reticulum kinase(PERK), inositol requiring enzyme 1 alpha(IRE1α), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP) in bone tissue. Western blot was used to detect the protein expression of glucose-regulated protein 78 (GRP78), PERK, IRE1α, ATF6, CHOP and mitofusin 2 (MFN2). Results TUNEL results showed that Qiang Gu Kang Wei Extraction inhibited apoptosis. RT-PCR results showed that, compared with the control group, the content of PERK were significantly higher in the simulated weightlessness rgoup (P<0.05), while the PERK in the Qiang Gu Kang Wei Extraction group were significantly lower(P<0.05). Western blot results showed that, compared with the control group, the content of GRP78, PERK, CHOP and ATF6 were significantly higher and MFN2 was decreased in the simulated weightlessness rgoup(P<0.05), while the GRP78, PERK, CHOP and ATF6 were significantly lower and MFN2 was increased in the Qiang Gu Kang Wei Extraction group(P<0.05). Conclusion The Qiang Gu Kang Wei Extraction can reduce bone cells apoptosis of simulated weightlessness rats through inhibiting GRP78, PERK, ATF6 and CHOP, as well as upregulating MFN2 expression in bone tissue, thereby reducing bone loss under weightlessness condition.