Keratin, a core structural protein in epithelial cells, is essential for maintaining epithelial tissue integrity. Numerous studies have confirmed its critical role in proliferative disorders, including lung/liver cancer, idiopathic pulmonary fibrosis (IPF), and hepatic fibrosis (HF). Post-translational modification (PTM) regulates protein activity, and keratin undergoes phosphorylation, acetylation, and methylation—modifications that modulate fibrosis and cancer progression by regulating relevant signaling pathways. However, how these modifications reshape keratin’s structure and function in these diseases remains understudied, underscoring the necessity for a systematic review. This review first summarizes keratin’s classification, physiological functions, and roles in epithelial cells, then focuses on the physiological significance of keratin modifications in fibrosis and cancer, while dissecting the molecular mechanisms by which keratin PTMs drive disease progression to address the knowledge gap regarding modification-related keratin changes. Elucidating the mechanisms of keratin and its PTMs is pivotal for understanding disease progression and developing targeted therapies; meanwhile, keratin-targeted strategies—such as keratin siRNAs and small-molecule compounds that regulate keratin expression or modification—have shown therapeutic potential. In summary, this review synthesizes current research findings and provides novel insights for the treatment of fibrosis and cancer.