Objective This study aimed to preliminarily investigate the mechanism by which Sanqiang formula acts on quadriceps muscle atrophy in unstable knee osteoarthritis ( KOA), and to provide experimental evidence for its clinical application and development. Methods The KOA rat model was established by transection of the anterior cruciate ligament (ACL) of the right posterior knee joint. In the Sham operation group, only the skin was incised, and the ACL was completely preserved. The successfully modeled rats were divided into the Model group, celecoxib group, and low-, medium-, and high-dose Sanqiang formula groups, with ten rats in each group.The Sham operation and model groups were administered normal saline by gavage; the other groups were administered the corresponding doses of the drug by gavage. Behavioral tests were conducted before and after drug administration.After the end of administration, the passive range of motion of the rat knee joint was measured; the quadriceps femoris muscle weight, and serum interleukin ( IL )-1β and tumor necrosis factor ( TNF )-α levels were determined.Hematoxylin-eosin staining was used to observe quadriceps muscle tissue damage in SD rats of each group, and Masson staining was used to observe quadriceps muscle fibrosis changes. RT-qPCR was used to detect the expression of Atrogin-1 and MuRF1 mRNA in skeletal muscle tissues of each group; Western blot was used to detect the expression of PI3K, p-PI3K, AKT, p-AKT, FOXO1, p-FOXO1, Atrogin-1, and MuRF1 proteins in skeletal muscle tissues of each group. Results Sanqiang formula improved behavioral changes in rats ( P<0. 05, P<0. 001),significantly increased passive range of motion (P<0. 001), and increased quadriceps muscle weight (P<0. 05). It decreased serum IL-1β and TNF-α (P<0. 01, P<0. 001), increased muscle cell area in the medium- and high-dose groups (P<0. 001), significantly reduced interstitial connective tissue among groups, and reduced collagen volume fraction ( P<0. 001 ). Treatment improved pathological morphological changes in articular cartilage, increased p-PI3K/ PI3K, p-AKT / AKT, and p-FOXO1 / FOXO1 values in quadriceps muscle (P<0. 05, P<0. 01, P<0. 001),and inhibited Atrogin-1 and MuRF1 protein and mRNA expression in quadriceps muscle ( P<0. 01, P<0. 001). Conclusions Sanqiang formula promoted the activation of PI3K/ AKT / FOXO1 signaling in the quadriceps muscle of KOA rats, inhibited the expression of Atrogin-1 and MuRF1, and improved quadriceps muscle atrophy.