Aim Muscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles but the understanding of underlying mechanisms and muscle‐specific differences remains incomplete. This study aims at investigating the temporal expression and phosphorylation of the Janus kinase / signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition in order to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition. Methods A novel experimental ICU model allowing long‐term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralyzed by post‐synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle‐specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles. Results The JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle‐specific differences were observed in the temporal activation pattern between plantaris, intercostal, and diaphragm muscles. Conclusion The JAK2/STAT3 pathway was differentially activated in plantaris, intercostal, and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle‐specific effects on muscle mass and function in response to both short‐ and long‐term exposure to the ICU condition prior to the translation into clinical research and practice. This article is protected by copyright. All rights reserved.