Osteoporosis is the most common metabolic bone disorder affecting up to 40% of postmenopausal women, characterized by a reduction in bone mass leading to bone fragility and fractures. Herbal medication has been and remains commonly used instead of chemical drugs because of its minor side effects. Lepidium sativum L. (LS) or “hab arachad", is a native shrub, which is well known as a good alternative medication for fracture healing. The aim of this study is to evaluate the effect LS extract loaded chitosan nanoparticles on gene expression of miR-142-3p and miR-23a in experimental rat model of osteoporosis. The osteoporosis was induced in rats by subcutaneous injection with methylprednisolone (3.5 mg/kg b.wt / day) for 4 weeks. Then osteoporotic rats were orally treated with 400 mg/kg b.wt /day LS extract, chitosan nanoparticles (CN) and 400 mg/kg b.wt /day LS extract loaded on chitosan nanoparticles for 12 weeks. Our results showed that treatment with LS, CN and LS loaded on CN ameliorated the biochemical bone indices with variable degrees, with a net results of enhanced serum calcium and phosphorus. Treated rats showed a significant decrease in the expression of miR-23a and a significant increase in the expression of miR-142-3p which emphasized the improvement of osteoporosis. The effect of treatment with LS and LS loaded on CN was confirmed by histopathological observations. All of these effects together with the safety and no adverse effects of LS and LS loaded on CN make it a promising therapeutic agent for management of Osteoporosis.