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In patients with myositis, persistent skeletal muscle weakness in the absence of significant inflammatory cell infiltrates is a well-recognised, but poorly understood, cause of morbidity. This has led researchers to investigate cellular mechanisms independent of immune cells, which may contribute to this underlying muscle weakness. Chronic ER stress pathway activation is evident in the muscle of myositis patients, and is now a potential mediator of muscle weakness in the absence of inflammation. Abnormal ER stress pathway activation is associated with mitochondrial dysfunction, resulting in bioenergetic deficits and reactive oxygen species (ROS) generation, which in this context may potentially damage muscle proteins and thus impair contractile performance. This study examined whether treatment with the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17AAG) could mitigate these ER stress-induced changes. C2C12 myotubes were treated with the ER stress-inducing compound Tunicamycin, in the presence or absence of 17AAG. Myotubes were examined for changes relating to ER stress pathway activation, mitochondrial function, markers of oxidative damage and in myotubular dimensions. ER stress pathway activation caused mitochondrial dysfunction, as evidenced by reduced oxygen consumption and ATP generation and by increased gene expression levels of the bio-energetic regulator, uncoupling protein 3 (UCP-3), the latter indicative of electron transport chain uncoupling. ER stress pathway activation also caused increased gene expression of superoxide dismutase (SOD) 2 and peroxiredoxin (PRDX) 3, elevated H2O2 levels, and reduced total thiol pool levels and a significant diminution of myotubular dimensions. Exposure to 17AAG ameliorated these ER stress-induced changes. These findings, which suggest that 17AAG can reduce ER stress-induced mitochondrial dysfunction, oxidative damage and myotubular atrophy, have potential implications in the context of human myositis.