Objective To explore the mechanism by which Sijunzi Tang improves osteosarcopenia (OS) in rats based on the Toll-like receptor 4 ( TLR4) / nuclear factor (NF)-κB pathway. Methods Rats were divided randomly into sham, OS, Sijunzi Tang L, Sijunzi Tang H, estradiol, and Sijunzi Tang H+lipopolysaccharide (LPS) groups. The OS model was constructed by castration combined with intraperitoneal injection of dexamethasone. After treatment with Sijunzi Tang and the TLR4 activator LPS, 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 histopathological examination of femur tissues and quadriceps femoris tissue was carried out by hematoxylin / eosin staining. The cross-sectional area (CSA) of quadriceps muscle fibers was compared. Serum procollagen I N-terminal propeptide ( PINP ), C-telopeptide of type I collagen ( CTX-1 ),osteocalcin (OCN), and inflammatory factors were determined by enzyme-linked immunosorbent assay. TLR4 / NF-κB pathway proteins in the quadriceps femoris and femur tissues were detected by immunohistochemical staining and Western blot. Results In the sham surgery group, OS rats showed decreased forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, BV/ TV, BS / TV, Tb. N, quadriceps mass fraction, muscle fiber CSA, and levels of PINP and OCN (P<0. 05), and increased Tb. SP, levels of CTX-1, interleukin (IL)-6, IL-1β and IL-17, positive expression of TLR4 and phospho (p)-NF-κB p65, TLR4 protein expression, and p-NF-κB p65 / NF-κB p65 (P<0. 05). For the OS group, rats in the Sijunzi Tang L group,Sijunzi Tang H group and estradiol group showed increases 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, levels of PINP and OCN (P<0. 05), and decreases in Tb. SP, levels of CTX-1, IL-6, IL-1β and IL-17, positive expression of TLR4 and p-NF-κB p65, TLR4 protein expression and p-NF-κB p65 / NF-κB p65 (P<0. 05). Sijunzi Tang H and estradiol groups, however, had a stronger improving effect on various pathological indicators in OS rats. Rats in the Sijunzi Tang H + LPS group showed decreased forelimb muscle strength, whole-body and femoral bone densities, muscle percentage, BV/ TV, BS / TV,Tb. N, quadriceps mass fraction, and muscle fiber CSA, and decreased levels of PINP and OCN (P<0. 05), and increased Tb. SP, levels of CTX-1, IL-6, IL-1β, and IL-17, positive expression of TLR4 and p-NF-κB p65, TLR4 protein expression and p-NF-κB p65 / NF-κB p65 (P<0. 05). There was no significant difference in various indicators between Sijunzi Tang H group and estradiol group ( P>0. 05). Conclusions Sijunzi Tang can improve muscle atrophy and osteoporosis symptoms in OS rats by suppressing activation of the TLR4 / NF-κB signaling pathway.