Spaceflight causes astronauts to experience an unbalanced level of bone remodeling favoring resorption. The combination of an antiresorptive drug and weightlessness may have negative effects on the mechanical and structural properties of bone by increasing elastic stiffness but diminishing plasticity. At 16 weeks of age, skeletally postpubescent male mice (n = 32, C57BL/6) were evenly divided and subcutaneously given either zoledronate (45 µg/kg) or vehicle (saline, same volume). Three days postinjection, half of each group were divided to undergo 3 weeks of hindlimb unloading or act as a control undergoing normal ambulation (n = 8 for each of the 4 groups). Ex vivo µCT assays showed zoledronate preserving cancellous mineral, bone, and cortical bone. Hindlimb unloading reduced cortical bone. Three-point bending of the femoral mid-shaft showed zoledronate increased stiffness, ultimate force, and total energy (+28%, +17%, +15%, respectively). Hindlimb unloading reduced stiffness but increased postyield displacement, a measurement of plasticity (-29%, +20%, respectively). The combined treatment resulted in increased stiffness, with zoledronate not modulating the hindlimb unloading main effect on postyield displacement. Though stiffness increased, contrary to the hypothesis, the combination of zoledronate and hindlimb unloading did not result in a decreased plasticity