<p>The YEATS domain proteins act as epigenetic readers that recognize histone acylation marks and play vital roles in transcriptional regulation. In recent years, emerging evidence has revealed their involvement in various cancers, including glioblastoma, breast cancer, and liver cancer, where they contribute to tumor progression, drug resistance, and metastasis, highlighting their potential as therapeutic targets. This review first outlines the molecular functions of YEATS domain proteins, emphasizing their roles in chromatin remodeling, histone modification, transcription elongation, and DNA repair. We then focus on the involvement of YEATS family members—such as ENL, AF9, YEATS2, and YEATS4—in digestive system tumors, including hepatocellular carcinoma, pancreatic cancer, gastric cancer, and colorectal cancer. Their abnormal expression and oncogenic functions are discussed in detail. Furthermore, we summarize the regulatory interactions between YEATS domain proteins and key oncogenic signaling pathways in digestive tumors, such as the NOTCH signaling pathway, p21 regulatory factor, HIF1α, and Wnt/β-Catenin pathway, which contribute to tumor cell proliferation, migration, and stemness maintenance. Overall, this review provides a comprehensive overview of the epigenetic functions and tumor-promoting mechanisms of YEATS domain proteins, especially in digestive system tumors, and highlights their potential as promising targets for the development of selective small-molecule inhibitors.</p>