Significance Skeletal muscle is composed of multinucleated myofibers that are essential for movement and metabolism. Duchenne muscular dystrophy (DMD) is a devastating disease that is caused by the lack of the dystrophin protein, which maintains the integrity of muscle membranes. The absence of dystrophin results in myofiber degeneration followed by regeneration until muscle stem cells are depleted. We generated a new DMD mouse model lacking exon 51 and then used single-nucleus RNA sequencing to reveal the transcriptional diversity of individual myofiber nuclei in dystrophic muscle compared to normal muscle. Our findings uncover disease-associated pathways responsible for muscle degeneration and regeneration that might ultimately be manipulated therapeutically and reveal an unrecognized regenerative myonuclear population associated with dystrophic muscle.