The double‐stranded RNA‐dependent protein kinase (PKR) contributes to inflammatory cytokine expression and disease pathogenesis in many conditions. Limited data are available on the efficacy of the PKR inhibitor imoxin to prevent lipopolysaccharide (LPS)‐induced inflammation in skeletal muscle in vivo. The aim of this study was to evaluate the effect of imoxin, a PKR inhibitor, on inflammatory and atrophy signaling in skeletal muscle in response to an acute inflammatory insult with LPS. Six‐week old C57BL/6J mice received vehicle (saline) or 0.5 mg/kg imoxin 24 and 2 h prior to induction of inflammation via 1 mg/kg LPS. Gastrocnemius muscles were collected 24 h post‐LPS and mRNA and protein expression were assessed. LPS lead to a loss of body weight, which was similar in Imoxin+LPS. There were no differences in muscle weight among groups. LPS increased gastrocnemius mRNA expression of TNF‐α and IL‐1β, and protein levels of NLRP3, all of which were attenuated by imoxin. Similarly, IL‐6 mRNA and IL‐1β protein were suppressed in Imoxin+LPS compared to LPS alone. LPS increased mRNA of the atrogenes, MuRF1 and MAFbx, and imoxin attenuated the LPS‐induced increase in MuRF1 mRNA, and lowered MuRF1 protein. Imoxin+LPS increased p‐Akt compared to saline or LPS, whereas p‐mTOR was unaltered. FoxO1 was upregulated and p‐FoxO1/FoxO1 reduced by LPS, both of which were prevented by imoxin. Both LPS and Imoxin+LPS had diminished p‐FoxO3/FoxO3 compared to control. These results demonstrate the potential anti‐inflammatory and anti‐atrophy effects of imoxin on skeletal muscle in vivo.