With the aging of the population and the concomitant increase in obesity rates, the medical and socioeconomic impacts of osteoporosis are expanding rapidly. Medium-chain triglycerides (MCT) and high-oleic peanut oil (HOP) are dietary fats with evidenced metabolic benefits, including weight management and regulation of glucose-lipid homeostasis metabolism. However, the differences in efficacy and underlying mechanisms between MCT and HOP in osteoporosis are still unclear. In this study, the osteoporosis mice induced by high-fat diet were treated with MCT and HOP for nine weeks. The results showed that both MCT and HOP reduced body weight, elevated bone mineral density and bone biomechanical quality, and improved the adverse changes of stroma and trabecular in the bone marrow to some extent, in which HOP exhibited more effective effects. Mechanistically, HOP treatment activated the PI3K/AKT and ERK signaling pathways and upregulated Runx2 expression, thereby promoting osteogenic differentiation of bone mesenchymal stem cells. In summary, HOP exhibited superior efficacy in improving osteoporosis induced by obesity compared to MCT, whereas MCT was more conducive to weight loss without compromising bone health. These results provide new evidence for the use of HOP and MCT in patients with osteoporosis.