In the present study, the estrogenic activity and anti-osteoclastogenic activity of the Myelophycus simplex extract were evaluated using T47D-Kbluc cells and bone marrow-derived macrophages (BMMs). As a result of the measurement of the estrogenic activity in the T47D-Kbluc cell line, the Myelophycus simplex extract showed increased estrogenic activity in a dose-dependent manner in association with its concentration. To confirm the regulatory effect of the Myelophycus simplex extract on the estrogen-responsive gene, the Myelophycus simplex extract showed a similar tendency to estradiol: the expression of estrogen receptor 1 (ESR1) was significantly decreased while the expression of estrogen receptor 2 (ESR2) was increased. Furthermore, the Myelophycus simplex extract exhibited an inhibitory effect on osteoclast differentiation. In conclusion, these Myelophycus simplex extracts might be regarded as candidates for further studies or the development of functional food products or medicine to prevent or avoid postmenopausal symptoms for women.