Holothurin A (HA) and Echinoside A (EA) are the most abundant monomers in sea cucumber saponins, exhibiting different structures only in the side chain at position 20. However, although sea cucumber saponins have been proved to have osteogenic activity, the effect and structure-activity relationship of sea cucumber saponins to improve osteoporosis remain unknown. In the current study, mice with ovariectomization-induced osteoporosis were orally administered with HA and EA for 90 days. The result showed that both HA and EA reduced the levels of serum osteogenesis markers ALP, collagen I, and OCN and bone resorption markers MMP-9, Cath-K and TRAP, and thus inhibited the high bone turnover induced by ovariectomy. Furthermore, we found that HA and EA increased the bone mineral density and apposition rate, reversed the loss of trabecular bone and bone marrow stroma, in which EA exhibited more effective effects. CB1 and MKP-1 are the targets of the glucocorticoid-like effect of saponins. PCR and western blot results indicated that HA and EA alleviated overactive osteogenesis via stimulating CB1 and MKP-1, downregulating the PI3K/AKT/β-catenin signal pathway. The OPG/RANKL/NF-κB pathway was identified as a critical regulator of bone resorption. Further investigation revealed that HA and EA significantly downregulate the expression of IKK, NF-κB and phosphorylated NF-κB p65, suppressing the expression of osteoclastogenesis transcription factors c-fos and NFATC1. To the best of our knowledge, this is the first report showing that both HA and EA improved osteoporosis, and these activities depend on the structure of saponins. These findings would provide guidance for the application of saponins in the management of osteoporosis.