Leonurus sibiricus L. (LS) is a medicinal plant used in East Asia, Europe and the USA. LS is primarily used in the treatment of gynecological diseases, and recent studies have demonstrated that it exerts anti‑inflammatory and antioxidant effects. To the best of our knowledge, the present study demonstrated for the first time that LS may promote osteoblast differentiation and suppress osteoclast differentiation in vitro, and that it inhibited lipopolysaccharide (LPS)‑induced bone loss in a mouse model. LS was observed to promote the osteoblast differentiation of MC3T3‑E1 cells and upregulate the expression of runt-related transcription factor 2 (RUNX2), a key gene involved in osteoblast differentiation. This resulted in the induction of the expression of various osteogenic genes, including alkaline phosphatase (ALP), osteonectin (OSN), osteopontin (OPN), type I collagen (COL1) and bone sialoprotein (BSP). LS was also observed to inhibit osteoclast differentiation and bone resorption. The expression levels of nuclear factor of activated T‑cells 1 (NFATc1) and c‑Fos were inhibited following LS treatment. NFATc1 and c‑Fos are key markers of osteoclast differentiation that inhibit receptor activator of nuclear factor‑κΒ ligand (RANKL)‑induced mitogen‑activated protein kinase (MAPKs) and nuclear factor (NF)‑κB. As a result, LS suppressed the expression of osteoclast‑associated genes, such as matrix metallopeptidase‑9 (MMP‑9), cathepsin K (Ctsk), tartrate‑resistant acid phosphatase (TRAP), osteoclast‑associated immunoglobulin‑like receptor (OSCAR), c‑src, c‑myc, osteoclast stimulatory transmembrane protein (OC‑STAMP) and ATPase H+ transporting V0 subunit d2 (ATP6v0d2). Consistent with the in vitro results, LS inhibited the reduction in bone mineral density and the bone volume/total volume ratio in a mouse model of LPS‑induced osteoporosis. These results suggest that LS may be a valuable agent for the treatment of osteoporosis and additional bone metabolic diseases.