QiangGuYin (QGY) is a common Traditional Chinese medicine prescription for the treatment of osteoporosis. Previous clinical studies have found that QGY effectively improves bone mineral density (BMD) in postmenopausal women, but its underlying mechanism remains unclear. The osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK) pathway is a classic pathway involved in osteoporosis. Secretin levels are a serum marker of osteoporosis, but their effect on the OPG/RANKL/RANK pathway has not been reported. Hence, we investigated the relationship between the OPG/RANKL/RANK pathway and secretin and further revealed the mechanism underlying the effect of QGY in the treatment of osteoporosis. Mice were divided into secretin knockdown, secretin overexpression, and corresponding control groups. Micro-computed tomography was used to detect BMD in different groups, and the results show that QGY significantly improved BMD in mice of the secretin knockdown group. To further verify this, the serum levels of OPG, RANKL, RANK, and secretin were measured by enzyme-linked immunosorbent assays, and femur levels of OPG, RANKL, RANK, and secretin were evaluated by real-time quantitative PCR and western blotting. The results show that the expression of OPG was inhibited and that of RANKL and RANK was increased in mice from the secretin knockdown group, whereas the expression of OPG was upregulated and that of RANKL and RANK was downregulated after QGY intervention. Therefore, QGY inhibited bone resorption by promoting the expression of secretin and modulating the OPG/RANKL/RANK pathway. In addition to the effect of QGY, we also revealed the general regulatory effect of secretin on the OPG/RANKL/RANK pathway. We conclude that QGY modulates the OPG/RANKL/RANK pathway by increasing secretin levels during treatment of primary type I osteoporosis. This work provides a theoretical basis for the clinical use of QGY in the treatment of osteoporosis.