Osteoporosis is a silent disease that leads to fragility fractures that can diminish quality of life and contribute to death. With no ideal drug treatment available to manage osteoporosis, soy isoflavones (ISO), and omega-3 long chain PUFAs in fish oil (FO) may be integral in a dietary strategy that prevents bone loss. The overall objective of this study was to determine if combining ISO with omega-3 long chain PUFAs resulted in greater protection against the loss of bone mineral and skeletal weakening in ovariectomized mice. Ovariectomized CD-1 mice were randomized to control diet or a diet containing ISO alone (250 mg of genistein + 250 mg of daidzein/kg diet), FO alone (7% menhaden oil), or ISO + FO. Each dietary intervention prevented the loss of bone mineral density (BMD) in the femur and preserved femur strength, but only FO, either alone or combined with ISO, resulted in a higher BMD of lumbar vertebra (LV). Most notably, FO + ISO resulted in a higher peak load of LV4, indicating that vertebra were more resistant to fracture. Whether a dietary strategy providing FO in combination with ISO attenuates bone loss in postmenopausal women awaits investigation.