Objective To observe the effect of Sanqiang Formula on the quadriceps femoris muscle in a rat model of knee osteoarthritis (KOA), and to further explore the changes in proliferation- and apoptosis-related proteins and mRNA in the PI3K-AKT-FOXO1 signaling pathway, in order to preliminarily investigate the mechanism by which Sanqiang Formula acts on quadriceps muscle atrophy in unstable KOA, and to provide experimental evidence for the clinical application and development of this formula. Method 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 10 rats in each group. The sham operation group and the model group were administered normal saline by gavage, while 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 (ROM) of the rat knee joint was measured; the quadriceps femoris muscle weight, and serum IL-1β and TNF-α levels were determined; HE staining was used to observe quadriceps muscle tissue damage in SD rats of each group; Masson staining was used to observe quadriceps muscle fibrosis changes; HE staining was used to observe quadriceps muscle tissue damage in SD rats of each group; RT-qPCR was used to detect the expression of Atrogin-1 and MuRF1 mRNA in skeletal muscle tissues of each group; Western blotting 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. Rusults Sanqiang Formula improved behavioral changes in rats (P<0.05, P<0.001); significantly increased passive range of motion (P<0.001); increased quadriceps muscle weight; decreased serum levels of IL-1β and TNF-α (P<0.001); increased muscle cell area in the medium- and high-dose groups (P<0.001); significantly reduced the content of interstitial connective tissue among groups and reduced collagen volume fraction (P<0.001); Improves the pathological morphological changes of 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); inhibited the expression of Atrogin-1 and MuRF1 proteins and mRNA in quadriceps muscle (P<0.01, P<0.001). Conclusions Sanqiang Formula can promote the activation of the PI3K-AKT-FOXO1 signaling pathway in the quadriceps muscle of KOA rats, inhibit the expression of Atrogin-1 and MuRF1, and improve quadriceps muscle atrophy.