Histone deacetylases (HDACs) are critical regulators of both histone and non-histone proteins, influencing various cellular processes, including gene expression, cell proliferation, and fibrosis. This review provides a comprehensive analysis of the role of HDACs in fibrotic diseases affecting multiple organs, including the liver, kidney, heart, lung, and colon. We discuss the distinct contributions of different HDAC classes and the mechanisms by which they promote fibrosis, highlighting both histone-dependent and independent pathways. Furthermore, we summarize current advances in the development of HDAC inhibitors and their potential as therapeutic agents for fibrosis. Ongoing clinical trials targeting HDACs in fibrotic diseases are also reviewed, underscoring the translational relevance of preclinical findings. Finally, we propose future research directions, emphasizing the need for selective HDAC inhibitors and combination therapies that may enhance therapeutic efficacy and reduce side effects. This review aims to provide a solid foundation for future research and clinical applications of HDAC inhibitors in fibrosis treatment.