n cancer treatment regimens using chemotherapy, adverse effects can outweigh the benefits. Various chemotherapeutic drugs are linked to skeletal muscle wasting, drastically reducing the chance of survivability of cancer patients. Insights into the molecular basis of chemotherapy-induced cachexia is an unmet need to improve the treatment strategies. Here, we investigated tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents for their effects on muscle function. Sorafenib (Sor), but not Nilotinib (Nilo) and Imatinib (Ima), triggered cachexia. Our system-wide analyses revealed that Sor alters the global transcription program and proteostasis in muscle cells. Mechanistically, Sor impeded chromatin association of SET1/MLL histone methyltransferase on distinct muscle-specific genes. Thus, it reduced H3K4 methylation and rendered the chromatin transcriptionally incompetent, as characterized by diminished association of RNA polymerase II. This transcriptional reorientation resulted in disruption of sarcomere organization, drastically perturbed calcium homeostasis, and mitochondrial respiration in muscle cells. Consequently, Sor-treatment severely compromised the contractile ability of muscle cells. Collectively, we identified an unanticipated epigenetic process affected by Sor that led to cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced muscle wasting and improve treatment outcomes.