DMD and BMD are progressive dystrophinopathies characterized by ongoing muscle degeneration, metabolic dysregulation, and variable functional decline. Despite advances in glucocorticoid therapy and emerging dystrophin-restoring treatments, accurately monitoring disease progression and treatment response remains challenging. Clinical measures often lack sensitivity to early biochemical changes, whereas metabolites provide dynamic readouts linking muscle pathology to disease progression and therapeutic effects.The objective of this study was to investigate how longitudinal changes in metabolite expression reflect disease progression and treatment effects in dystrophinopathies, with a focus on muscle-relevant metabolic pathways. We aimed to determine whether specific metabolite trajectories could differentiate natural disease progression from pharmacologic modulation, particularly in response to glucocorticoid treatment.Longitudinal profiling of serum and urine samples revealed distinct metabolite expression patterns that evolved with disease severity and treatment exposure. Progressive alterations were observed in pathways related to muscle energy homeostasis, mitochondrial function, membrane integrity, and oxidative stress. Metabolites associated with muscle mass and turnover, including creatine–creatinine balance, showed consistent shifts over time, reflecting ongoing muscle loss. Amino acid–related metabolites and dipeptides involved in redox buffering and membrane stabilization demonstrated treatment-sensitive trends, suggesting partial metabolic modulation with glucocorticoid therapy. Lipid-associated metabolites, including those linked to fatty acid handling and sphingolipid metabolism, displayed divergent longitudinal trajectories, indicating differential effects of disease progression versus therapeutic intervention. Importantly, several metabolites exhibited distinct patterns under daily versus intermittent glucocorticoid regimens, highlighting treatment-specific metabolic remodeling rather than uniform suppression or normalization. Longitudinal metabolite trajectories reflect both disease progression and therapeutic effects in dystrophinopathies. Alterations in muscle-associated pathways provide sensitive indicators of disease state and treatment response beyond conventional clinical measures, supporting the use of metabolomics for biomarker development and personalized monitoring in DMD and BMD.