Cortisol, the principal glucocorticoid in teleosts, coordinates the physiological response to stress by regulating metabolism, protein turnover, and growth. Although the molecular effects of acute cortisol exposure have been extensively characterized, the epigenomic mechanisms underlying skeletal muscle remodeling during prolonged cortisol elevation remain poorly understood. Here, we investigated how chronic cortisol reshapes chromatin accessibility and gene expression in rainbow trout (Oncorhynchus mykiss) skeletal muscle using an integrative ATAC-seq and RNA-seq approach. Fish received a single intraperitoneal injection of cortisol (50 μg g⁻¹ body weight) formulated in coconut oil for sustained hormone release and were sampled after 14 days. Cortisol treatment significantly increased plasma cortisol levels, reduced specific growth rate, and increased skeletal muscle protein carbonylation, indicating impaired growth and oxidative protein damage. ATAC-seq revealed extensive chromatin remodeling, including 126,780 cortisol-specific accessible regions and 3393 genes associated with increased accessibility. These genes were enriched in pathways related to FoxO signaling, autophagy, and apoptosis, whereas regions with reduced accessibility were associated with TGF-β signaling, extracellular matrix interactions, and muscle structural maintenance. RNA-seq identified 2170 differentially expressed genes (844 upregulated and 1326 downregulated), revealing a parallel transcriptional shift toward protein turnover, autophagy, and metabolic adaptation, together with repression of extracellular matrix organization, focal adhesion, integrin signaling, and cytoskeletal organization. Integrative analysis identified 113 genes with coordinated increases and 46 genes with coordinated decreases in chromatin accessibility and transcript abundance, highlighting ubiquitin-mediated proteolysis, mitophagy, FoxO signaling, and metabolic pathways as core components of the chronic cortisol response. Collectively, these findings demonstrate that sustained cortisol elevation drives coordinated epigenomic and transcriptomic remodeling of skeletal muscle, promoting a catabolic phenotype characterized by enhanced protein turnover, oxidative protein damage, and impaired structural maintenance, ultimately contributing to reduced growth and potentially compromising fish welfare under aquaculture conditions.