Duchenne muscular dystrophy (DMD) is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models, and the HDACi Givinostat has shown promise for DMD in clinical trials. However, beyond a small group of HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Using an established animal model for DMD, the zebrafish dmd mutant strain sapje, we screened a library of over 800 epigenetic small molecules of various classes. We used a quantitative muscle birefringence assay to assess and compare the effects of these small molecule treatments on dmd mutant zebrafish skeletal muscle. Our screening identified already-established HDACi, as well as new HDACi, that ameliorated dmd mutant zebrafish skeletal muscle degeneration. We find that a single early treatment of HDACi can ameliorate dmd zebrafish. Furthermore, we find that HDACi improve the function of 3-D engineered muscle tissues derived from DMD hiPSCs. Our results provide further support for the effectiveness of small-molecule screening in dmd zebrafish. Our results also add to the growing evidence that HDACi are promising candidates for treating DMD.