Objective To observe the effects of “Qiang Gu Kang Wei” extractive on bone tissue apoptosis and endoplasmic reticulum stress in tail-suspended rats, and to explore the mechanism of “Qiang Gu Kang Wei” extractive in preventing bone loss in simulated weightlessness. Methods 60 SD rats were randomly divided into control group, simulated weightlessness group (model group), “Qiang Gu Kang Wei” extractive group, Alendronate sodium group and “Gushukang”granule group, with 12 rats in each group. The tail suspension was used to simulate weightlessness. The treatment groups were given 0.24g/100g “Qiang Gu Kang Wei” extractive, 0.7mg/100g Alendronate sodium and 0.026g/100g “Gushukang”granule by gavage for 28 days, respectively. Control group and model group were given equal volume of normal saline. After 4 weeks of intragastric administration, rats were sacrificed, and the apoptosis of bone tissue cells was detected by TUNEL. RT-PCT 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” extractive inhibited apoptosis. RT-PCR results showed that, compared with the control group, the content of PERK were significantly higher in the model group (P<0.05), while the PERK in the “Qiang Gu Kang Wei” extractive group were significantly lower (P<0.05). Compared with the model group, the contents of GRP78, PERK, CHOP, ATF6 and MFN2 in the “Qiang Gu Kang Wei” extractive group were significantly decreased (P<0.05). Conclusion The “Qiang Gu Kang Wei” extractive can improve bone tissue 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.