Astronauts in space are exposed to radiation while weightless, which may contribute to subsequent bone loss. Gamma irradiation of post-pubertal mice rapidly increases the number of bone-resorbing osteoclasts and causes bone loss in cancellous tissue; similar changes also occur in skeletal diseases associated with oxidative stress. Therefore, we hypothesized that increased oxidative stress mediates radiation-induced bone loss and that musculoskeletal disuse changes the sensitivity of cancellous tissue to radiation exposure. Musculoskeletal disuse by hindlimb unloading (1 or 2 weeks) or total body gamma irradiation (1 or 2 Gy of ¹³⁷Cs) of four-month old, male C57Bl/6 mice each decreased cancellous bone volume fraction in the proximal tibiae and lumbar vertebrae. The extent of irradiation-induced acute cancellous bone loss in both tibiae and lumbar vertebrae was similar in normally loaded and hindlimb unloaded mice. Similarly, osteoclast surface in the tibiae increased 46% due to irradiation, 47% due to hindlimb unloading, and 64% due to irradiation and hindlimb unloading combined, when compared to normally loaded mice. Irradiation, but not hindlimb unloading, reduced viability and increased apoptosis of marrow cells and caused oxidative damage to lipids within mineralized tissue. Irradiation also stimulated ROS generation in marrow cells. Furthermore, injection of -lipoic acid, an anti-oxidant, mitigated the acute bone loss caused by irradiation. Together, these results showed that disuse and gamma irradiation, alone or combined, caused a similar degree of acute cancellous bone loss and share a common cellular mechanism of increased bone resorption. Furthermore, irradiation, but not disuse, may increase osteoclasts and acute bone loss via increased ROS production and ensuing oxidative damage, implying different molecular mechanisms. The finding that -lipoic acid protected cancellous tissue from the detrimental effects of irradiation has potential relevance to astronauts and radiotherapy patients.