Muscle atrophy is the loss of skeletal muscle mass during several pathological conditions such as long-term fasting, aging, cancer, diabetes, sepsis and immune disorders. Glucocorticoids are known to trigger skeletal muscle atrophy. Dexamethasone (DEX), a synthetic glucocorticoid, induces skeletal muscle atrophy by suppression of protein synthesis and promotion of protein degradation. The double-stranded RNA (dsRNA)-activated protein kinase R (PKR) plays a significant role in mediating lipopolysaccharide-induced inflammation. However, pathological roles of PKR in muscle atrophy are not fully understood. The current study aimed to investigate the effect of imoxin, a PKR inhibitor, on DEX-induced muscle atrophy in C2C12 myotubes. Myotubes were incubated with imoxin at different concentrations with or without 5 μM DEX for 24 h. In the current study, imoxin treatment significantly reduced protein levels of MuRF1 and MAFbx induced by DEX by 88 ± 2% and MAFbx by 99 ± 0%, respectively. Moreover, 5 μM imoxin treatment reduced protein ubiquitination by 42 ± 4% and protein content of nuclear FoxO3α (77 ± 4%) in presence of DEX. Furthermore, 5 μM imoxin treatment stimulated Akt phosphorylation (195 ± 5%), mTOR phosphorylation (171 ± 21 %) and p70S6K1 phosphorylation (314 ± 31 %) under DEX-treated condition even though DEX treatment did not suppressed Akt/mTOR/p70S6K1 axis. These findings suggest that imoxin may protect against DEX-induced skeletal muscle atrophy by alleviating muscle specific E3 ubiquitin ligases and imoxin alone may promote protein synthesis via Akt/mTOR/S6K1 axis in muscle cells.