Although Duchenne Muscular Dystrophy (DMD) is a progressive and degenerative disease there is evidence for embryonic and fetal stage defects during myogenesis, including transcriptional and epigenetic perturbations. Epigenetic small molecules are proving to be outstanding candidates as DMD therapies, they improve the phenotype in animal models, have a candidate in phase 3 clinical trials, and are already approved for use in cancers. However, many small molecule therapies for DMD have failed to show efficacy in clinical trials, which could be partly due to an inadequate preclinical evaluation or to targeting mechanisms too late in the disease. Human induced pluripotent stem cell (hiPSC) derived models recapitulate embryonic muscle development with high fidelity and enable characterization of contractile properties when cast into engineered muscle tissues (EMTs). Dystrophin-deficient EMTs were utilized to track the initiation and progression of pathology and then screened for functional recovery following treatment with novel epigenetic compounds identified in our high throughput DMD zebrafish screen. EMTs were repeatedly analyzed using the Magetometric Analyzer for eNgineered Tissue ARRAY (MANTARRAY) platform. Dystrophin-null EMTs showed force deficits, relaxation delays, elevated resting calcium, blunted calcium transients and impaired mitochondrial function. The histone deacetylase inhibitor Trichostatin A reversed the contractile deficit and corrected other aspects of the pathology in a dose-dependent manner. Single-cell transcriptomic profiling identified the deleterious molecular cascade downstream of dystrophin deficiency and provided insight into the corrective mechanisms of known and new therapeutic epigenetic modifiers. Our previous data showed that dystrophic muscle progenitors transcriptionally diverge during somitogenesis, which is marked by dysregulation in cell junction family of proteins and the regulators of cell state transitions. Combining developmental, structural and functional analyses at the engineered tissue level with the latest transcriptomic methods is improving our understanding the molecular drivers of DMD pathology and uncovering the mechanisms of new epigenetic therapeutics.