Osteoporosis can be classified as an inflammatory disease and the crosstalk between the immune system and bone growth should be considered. The effects of bovine lactoferrin on bone by osteoimmunology were investigated in the present study. Ten week old female BALB/c mice were ovariectomized (OVX) and fed for 12 weeks with a control diet or lactoferrin (2, 20 and 100 mg kg⁻¹ d⁻¹). The results showed that following 12 weeks of treatment after surgery, OVX resulted in bone loss, but treatment with lactoferrin preserved bone homeostasis. Lactoferrin significantly improved bone mineral density, and increased the serum levels of alkaline phosphatase, while it decreased the serum levels of tartrate-resistant acid phosphatase. Furthermore, according to micro-computed tomography (micro-CT), the bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) were elevated. The results indicated that the structure model index (SMI) was reduced in the OVX + LF groups. Additionally, lactoferrin enhanced the Max-Load and Max-Stress values of the femur, and increased the content of Ca and P. However, lactoferrin suppressed the RANKL/OPG ratio in OVX mice. Moreover, interferon-γ, interleukin-5 and interleukin-10 were elevated significantly in the OVX + LF groups. Lactoferrin had a positive effect on the bone micro-environment and might be a pleiotropic protein for the prevention and treatment of estrogen-dependent bone loss via the osteoimmunology pathway.