Hepatocellular carcinoma (HCC) is frequently associated with Yeats-domain containing 2 (YEATS2) overexpression, which enhances tumor progression via the PI3K/AKT pathway. Our study delineates YEATS2’s oncogenic functions in HCC and its potential as a prognostic and predictive biomarker. Through comprehensive in vitro and bioinformatics analyses, we reveal that YEATS2 promotes cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Additionally, YEATS2 modulates the tumor immune microenvironment and predicts response to immunotherapies and chemotherapies. YEATS2’s serum stability suggests its utility as a non-invasive biomarker for personalized HCC treatment.