Microgravity and its inherent reduction in body-weight associated mechanical loading encountered during spaceflight have been shown to produce deleterious effects on important human physiological processes. Rodent hindlimb unloading is the most widely-used ground-based microgravity model. Unfortunately, results from these studies are difficult to translate to the human condition due to major anatomic and physiologic differences between the two species such as bone microarchitecture and healing rates. The use of translatable ovine models to investigate orthopedic-related conditions has become increasingly popular due to similarities in size and skeletal architecture of the two species. Thus, a new translational model of simulated microgravity was developed using common external fixation techniques to shield the metatarsal bone of the ovine hindlimb during normal daily activity over an 8 week period. Bone mineral density, quantified via dual-energy X-ray absorptiometry, decreased 29.0% (p < 0.001) in the treated metatarsi. Post-sacrifice biomechanical evaluation revealed reduced bending modulus (–25.8%, p < 0.05) and failure load (–27.8%, p < 0.001) following the microgravity treatment. Microcomputed tomography and histology revealed reduced bone volume (–35.9%, p < 0.01), trabecular thickness (–30.9%, p < 0.01), trabecular number (–22.5%, p < 0.05), bone formation rate (–57.7%, p < 0.01), and osteoblast number (–52.5%, p < 0.001), as well as increased osteoclast number (269.1%, p < 0.001) in the treated metatarsi of the microgravity group. No significant alterations occurred for any outcome parameter in the Sham Surgery Group. These data indicate that the external fixation technique utilized in this model was able to effectively unload the metatarsus and induce significant radiographic, biomechanical, and histomorphometric alterations that are known to be induced by spaceflight. Further, these findings demonstrate that the physiologic mechanisms driving bone remodeling in sheep and humans during prolonged periods of unloading (specifically increased osteoclast activity) are more similar than previously utilized models, allowing more comprehensive investigations of microgravity-related bone remodeling as it relates to human spaceflight.