Disuse causes a rapid and substantial bone loss distinct in its pathophysiology from the bone loss associated with cancers, age, and menopause. While inhibitors of the activin-receptor signaling pathway (IASPs) have been shown to prevent ovariectomy- and cancer-induced bone loss, their application in a model of disuse osteopenia remains to be tested. Here, we show that a soluble activin type IIA receptor (ActRIIA-mFc) increases diaphyseal bone strength and cancellous bone mass, and mitigates the loss of femoral neck bone strength in the Botulinum Toxin A (BTX)-model of disuse osteopenia in female C57BL/6J mice. We show that ActRIIA-mFc treatment preferentially stimulates a dual-effect (anabolic-antiresorptive) on the periosteal envelope of diaphyseal bone, demonstrating in detail the effects of ActRIIA-mFc on cortical bone. These observations constitute a previously undescribed feature of IASPs that mediates at least part of their ability to mitigate detrimental effects of unloading on bone tissue. The study findings support the application of IASPs as a strategy to combat bone loss during disuse.