Objective: To explore the improvement mechanism of Sijunzi Tang on osteosarcopenia (OS) rats based on TLR4/NF-κB pathway. Methods: Rats were assigned into sham operation group, OS group, low-dose Sijunzi Tang group, high-dose Sijunzi Tang group, estradiol group and high-dose Sijunzi Tang+lipopolysaccharide (LPS) group randomly. The OS model was constructed by castration combined with intraperitoneal injection of dexamethasone. After treatment with Sijunzi Tang and TLR4 activator LPS, the forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, and distal femoral bone microstructure [percent bone volume (BV/TV), bone surface density (BS/TV), trabecular number (Tb.N), and trabecular separation degree (Tb.Sp)] were measured. The mass fraction of quadriceps muscle was detected, and HE staining was used for histopathological examination of quadriceps muscle tissue. The cross-sectional area (CSA) of quadriceps muscle fibers was compared. ELISA was used to measure serum procollagen i n-terminal propeptide (PINP), C-telopeptide of type I collagen (CTX-1), osteocalcin (OCN) ?and inflammatory factors. Immunohistochemical staining and immunoblotting was used to detect TLR4/NF-κB pathway proteins in the quadriceps femoris and femoral tissues. Results: For the sham surgery group, the OS group showed a decrease in forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, BV/TV, BS/TV, Tb.N, quadriceps mass fraction and muscle fiber CSA, the levels of PINP and OCN (P<0.05), and an increase in Tb.SP, the levels of CTX-1, IL-6, IL-1β and IL-17, positive expression of TLR4 and p-NF-κB p65, TLR4 protein expression, p-NF-κB p65/NF-κB p65 (P<0.05). For the OS group, the low and high-dose Sijunzi Tang groups, estradiol group showed an increase in forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, BV/TV, BS/TV, Tb.N, quadriceps mass fraction and muscle fiber CSA, the levels of PINP and OCN (P<0.05), and a decrease in Tb.SP, the levels of CTX-1, IL-6, IL-1β and IL-17, positive expression of TLR4 and p-NF-κB p65, TLR4 protein expression, p-NF-κB p65/NF-κB p65 (P<0.05). However, high-dose Sijunzi Tang and estradiol had a stronger improvement effect on various pathological indicators in OS rats. For the high-dose Sijunzi Tang group, the high-dose Sijunzi Tang+LPS group showed a decrease in forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, BV/TV, BS/TV, Tb.N, quadriceps mass fraction and muscle fiber CSA, the levels of PINP and OCN (P<0.05), and an increase in Tb.SP, the levels of CTX-1, IL-6, IL-1β and IL-17, positive expression of TLR4 and p-NF-κB p65, TLR4 protein expression, p-NF-κB p65/NF-κB p65 (P<0.05). There was no significant change in various indicators between the high-dose Sijunzi Tang group and the estradiol group (P>0.05). Conclusion: Sijunzi Tang can improve muscle atrophy and osteoporosis symptoms in OS rats by suppressing activation of TLR4/NF-κB signaling pathway.